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Growth hormone and insulin like growth factors are diabetogenic, so I assume that people with high growth hormone (say due to pituitary tumor) may be at high risk for diabetes. Has any correlation been established between these two? I know that diabetes is a multifactorial disorder and so only a correlation may be established.
That GH has an effect on glycaemic control is most evident from the abnormal glucose tolerance seen in acromegalics…
acromegalyis defined as
abnormal growth of the hands, feet, and face, caused by overproduction of growth hormone by the pituitary gland.
Such an effect has been known for decades, which makes sense given how interrelated the axes are. Although I think the best evidence is the fact that the side effects of growth hormone therapy says that
Some patients have developed diabetes mellitus…
Systems Biology-Derived Biomarkers to Predict Progression of Renal Function Decline in Type 2 Diabetes
Objective: Chronic kidney disease (CKD) in diabetes has a complex molecular and likely multifaceted pathophysiology. We aimed to validate a panel of biomarkers identified using a systems biology approach to predict the individual decline of estimated glomerular filtration rate (eGFR) in a large group of patients with type 2 diabetes and CKD at various stages.
Research design and methods: We used publicly available "omics" data to develop a molecular process model of CKD in diabetes and identified a representative parsimonious set of nine molecular biomarkers: chitinase 3-like protein 1, growth hormone 1, hepatocyte growth factor, matrix metalloproteinase (MMP) 2, MMP7, MMP8, MMP13, tyrosine kinase, and tumor necrosis factor receptor-1. These biomarkers were measured in baseline serum samples from 1,765 patients recruited into two large clinical trials. eGFR decline was predicted based on molecular markers, clinical risk factors (including baseline eGFR and albuminuria), and both combined, and these predictions were evaluated using mixed linear regression models for longitudinal data.
Results: The variability of annual eGFR loss explained by the biomarkers, indicated by the adjusted R 2 value, was 15% and 34% for patients with eGFR ≥60 and <60 mL/min/1.73 m 2 , respectively variability explained by clinical predictors was 20% and 31%, respectively. A combination of molecular and clinical predictors increased the adjusted R 2 to 35% and 64%, respectively. Calibration analysis of marker models showed significant (all P < 0.0001) but largely irrelevant deviations from optimal calibration (calibration-in-the-large: -1.125 and 0.95 calibration slopes: 1.07 and 1.13 in the two groups, respectively).
Conclusions: A small set of serum protein biomarkers identified using a systems biology approach, combined with clinical variables, enhances the prediction of renal function loss over a wide range of baseline eGFR values in patients with type 2 diabetes and CKD.
Growth Hormone Activates Gene Involved In Healing Damaged Tissue
Growth hormone is known to increase lean body mass and bone density in the elderly, but it does something else, too.
It activates a gene critical for the body's tissues to heal and regenerate, says Robert Costa, professor of biochemistry and molecular genetics at the University of Illinois at Chicago and a member of the UIC Cancer Center.
That discovery could help explain why we age.
"Growth hormone levels decline as we grow older as a result, the Foxm1b gene stops working and our bodies are less capable of repairing damage," Costa said.
In a paper published in the December issue of Hepatology, Costa and his colleagues report the results of studies on liver regeneration in aged (12-month-old) and young (2-month-old) mice -- a model system for studying the molecular mechanisms the body enlists to restore tissue damaged by injury or age. The liver is the only organ in the body capable of completely regenerating from mature cells.
The scientists focused on the Foxm1b gene, which is involved in the entire life cycle of the mammalian cell -- its proliferation, maturation and death. The gene's activity is elevated in dividing cells in young mammals but diminishes in old age.
In previous studies, the researchers inserted the human Foxm1b gene in aged mice whose livers had been partially removed (the two species have virtually identical forms of the gene). The experiments showed that the gene restored levels of Foxm1b proteins and induced the animals' livers to grow back at a rate typical of young mice. Further research detailed how the gene directs the busy molecular traffic inside cells to make them divide and multiply.
In the present study, the scientists tested the effects of human growth hormone because of its purported role in stimulating cell proliferation. Growth hormone, a substance secreted by the pituitary gland in the brain, is responsible for growth in children and young adults, but its levels decline during aging.
"The literature had suggested that growth hormone therapy in elderly men stimulates cells to divide," said Costa, leading to increases in muscle mass and skin thickness and greater bone density in the spine, while decreasing body fat.
"We wanted to find out how the hormone worked at a molecular level."
When aged mice whose livers had been partially removed were injected with human growth hormone, histological and other tests showed that the activity of the Foxm1b gene increased dramatically, as did levels of various enzymes and proteins that cause cells to divide. At the same time, the livers of these animals regenerated at a pace found in young mice. Cell proliferation peaked at just two days, and the liver was fully restored within a week.
By comparison, in aged mice that did not receive hormone injections, complete regeneration took a month or longer. Without growth hormone to turn on Foxm1b, the gene remained stuck at the low level of activity found in old age, and liver cells failed to multiply rapidly enough for a quick recovery.
Further tests were done with genetically engineered mice in whose liver cells the Foxm1b gene had been disabled. In these mice, growth hormone injections failed to stimulate recovery when the liver was partially removed.
"These results clearly demonstrate that Foxm1b is essential for growth hormone to spur liver regeneration," Costa said.
The study is apt to provide impetus for high-end clinics and spas already offering growth hormone injections to "treat" old age, but Costa is cautious about drawing any conclusions from his research about the merits of the therapy.
"Our liver regeneration studies tell us a great deal about how growth hormone works at a molecular level, but the injections occurred only over short periods of time, giving us no information about any long-term consequences," Costa said.
While several studies have shown that prolonged growth hormone therapy has dangerous side effects ranging from diabetes to carpal tunnel syndrome, Costa believes that short-term treatment with growth hormone could be used to speed repair after injuries or surgery in the elderly, shortening recovery time.
The National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute on Aging provided funding for the study. Other UIC scientists involved in the research were Katherine Krupczak-Hollis, Xinhe Wang and Margaret Dennewitz.
FASEB Science Research Conference: The Growth Hormone/Prolactin Family in Biology and Disease
Bethesda, MD - The FASEB Science Research Conference entitled "The Growth Hormone/Prolactin Family in Biology and Disease" focuses on the growth hormone (GH)/prolactin (PRL) family of hormones influence the progression of such major health problems as obesity, diabetes, aging, mental health and multiple cancers, in addition to their role in body growth and lactation. The conference seeks to bring together researchers and clinicians from academia and industry to share unpublished data and provide a forum for lively discussions amongst colleagues from as wide a set of backgrounds as possible. The objective is to improve our understanding of how GH/PRL family proteins modulate health and disease processes, and accelerate the discovery of new drugs.
The topics to be covered by the invited speakers include stem cells, pain, inflammation, angiogenesis, fetal programming, epigenetic regulation, new drug targets/pre-clinical studies, novel animal models, nanoscale techniques, and GH and PRL secretion, signaling, and regulation of gene transcription. A major aim is to nurture the careers of young investigators by providing the opportunity to present short talks and posters, and allowing ample opportunities for networking with invited speakers, other leaders in the field, and their peers.
FASEB has announced a total of 34 Science Research Conferences (SRC) in 2015. Registration opens January 20, 2015. For more information about an SRC, view preliminary programs, or find a listing of all our 2015 SRCs, please visit http://www. faseb. org/ SRC.
Since 1982, FASEB SRC has offered a continuing series of inter-disciplinary exchanges that are recognized as a valuable complement to the highly successful society meetings. Divided into small groups, scientists from around the world meet intimately and without distractions to explore new approaches to those research areas undergoing rapid scientific changes.
In efforts to expand the SRC series, potential organizers are encouraged to contact SRC staff at [email protected] Proposal guidelines can be found at http://www. faseb. org/ SRC.
FASEB is composed of 27 societies with more than 120,000 members, making it the largest coalition of biomedical research associations in the United States. Our mission is to advance health and welfare by promoting progress and education in biological and biomedical sciences through service to our member societies and collaborative advocacy.
Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.
Growth Hormone in Kids Linked to Risk of Diabetes
Feb. 18, 2000 (New York) -- Children who are given growth-hormone injections may be at a significantly increased risk of developing type 2 diabetes, according to a report in Saturday's issue of the journal The Lancet. Growth hormone is often prescribed for children whose pituitary glands do not make amounts of the hormone sufficient for normal growth. However, its use becomes controversial when it is given to children who are merely short-statured in order to boost their growth.
The New Zealand investigators say that the hormone injections may trigger early onset of diabetes in children who are already at risk of developing the disease later in life.
Type 2 diabetes develops when the cells in the body become resistant to the effects of insulin, the hormone that allows the blood sugar, or glucose, to be taken up into the cells and used for energy. This, in turn, leads to an accumulation of glucose in the blood. Type 2 diabetes is usually treated with diet and exercise, and in some cases, pills. Occasionally insulin injections are used if previous treatments do not control the blood sugar.
"We have always been worried about growth hormone exacerbating insulin resistance, and this is more evidence," says Allison Goldfine, MD, an investigator at Joslin Diabetes Center in Boston. "[The finding] stresses the importance of screening before giving growth hormone to identify glucose status and possibly monitoring periodically."
But Goldfine tells WebMD that it's important to put the findings into perspective, considering the psychological impact of withholding or refusing growth hormone to a child with severe growth retardation just because there is a possibility of developing diabetes.
The study included more than 20,000 Japanese children and adolescents age 19 and younger who were treated with growth hormone injections for an average of nearly three years. The average age at the start of growth hormone therapy was 10 years. Most children received growth hormone for less than three years.
Overall, the risk of diabetes was six times higher for the children who took growth hormone compared with the incidence in healthy U.S. and Japanese children not taking the hormone.
The authors say several possible explanations could account for the high incidence of type 2 diabetes reported in the study. "Although type 2 diabetes mellitus is thought to be rare in childhood and adolescence, there has been a substantial increase in the incidence of this disorder in the past few years," writes Wayne S. Cutfield, MD, a pediatric endocrinologist at the University of Auckland.
Another possibility is that the growth hormone may have hastened the onset of type 2 diabetes that would have occurred in adult life even if the children had not taken the hormone.
Stephen Gitelman, MD, director of the pediatric diabetes program at the University of California in San Francisco, says the findings are not overly surprising.
"We're seeing a real surge in type 2 diabetes in adolescents," Gitelman tells WebMD. "It's really reaching epidemic proportions. So we have this background where children are at increased risk as a result of ethnic diversity in our country and increased obesity, increased sedentary lifestyle, etc. And then on top of that you give a drug known to influence [glucose] metabolism and exacerbate insulin resistance. Given that background, it's not surprising that you are going to see a tendency toward more kids with diabetes."
But Gitelman says the possibility of diabetes developing during growth hormone treatment should always be discussed with parents, and if diabetes does develop, the shots either can be discontinued or the doses can be adjusted so as not to interfere with the diabetes.
Regulation of beta-cell mass by hormones and growth factors.
Substantial new information has accumulated on molecular mechanisms of pancreas development, regulation of beta-cell gene expression, and the role of growth factors in the differentiation, growth, and regeneration of beta-cells. The present review focuses on some recent studies on the mechanism of action of cytokines such as growth hormone (GH) and prolactin (PRL) in beta-cell proliferation and gene expression-in particular, the role of signal transducers and activators of transcription (STAT) proteins. The implication of the discovery of suppressors of cytokine signaling (SOCS) proteins for the interaction between stimulatory and inhibitory cytokines, including GH, PRL, leptin, and the proinflammatory cytokines interleukin-1 and interferon-gamma, in beta-cell survival is not yet clear. Recent studies indicate a role of cell adhesion molecules and the delta-like protein preadipocyte factor 1/fetal antigen 1 (Pref-1/FA-1) in cytokine-induced beta-cell growth and development. Surprisingly, glucagon-like peptide-1 (GLP-1) was recently found to stimulate not only insulin secretion but also beta-cell replication and differentiation, which may present a new perspective in treatment of type 2 diabetes. Together with the intriguing reports on positive effects of insulin on both beta-cell growth and function, a picture is emerging of an integrated network of signaling events acting in concert to control beta-cell mass adaptation to insulin demand.
Strategies that target GHR signaling
The most successful strategy to date for directly inhibiting GHR function has undoubtedly been peptide receptor antagonists, exemplified by the clinically used GHR antagonist pegvisomant (see below). However, therapeutic options to target the GHR are still limited, and pegvisomant can be difficult for researchers to access. Given the growing body of evidence that has suggested a role for this receptor in cancer and other diseases, there is certainly room for the development of alternative targeted therapeutics and several approaches are in preclinical and clinical development (Figs. 1 and 4, Table 1).
Strategies targeting the GHR One protein-derived GHR antagonist is clinically approved (pegvisomant), and several other GHR-targeted approaches are in development. These include an antagonist-GHBP fusion protein and anti-GHR antibodies, which inhibit the activation of GHR and block downstream signaling. Another approach is atesidorsen (ATL1103), an antisense oligonucleotide (ASO), that binds and induces the degradation of GHR mRNA. Small molecule compounds may also have applications however, there are currently limited reports in this area
Inhibitory strategies broadly fall into three categories: those that inhibit inhibition of GH secretion from the pituitary (pre-receptor), those that directly inhibit the GHR, and drugs which inhibit downstream components of GHR signaling pathways (post-receptor).
Inhibitors of GH secretion (pre-receptor)
Inhibitors of GH secretion include SRLs, dopamine agonizts and GHRH antagonists. 42,43,111 SRLs bind to the somatostatin receptors that are present in the tumor and suppress the secretion of GH from the pituitary. These inhibitors include the first-generation SRLs, octreotide and lanreotide, and the second-generation SRLs, pasireotide, octreolin, and somatoprim (Table 1). Currently, SRLs are used to treat acromegaly and neuroendocrine tumors. Other applications include diabetes, obesity and cancer. 112 SRLs also have direct anticancer activity through their actions on tumor cells that express somatostatin receptors, but it is unclear whether they suppress tumoral (autocrine/paracrine) secretion of GH.
Peptide GHRH analog antagonists have been developed in several labs. In particular, studies by Schally et al. 111 have led to a series of well-characterized inhibitors. 113 GHRH and GHRH receptors are expressed in many cancer cells and tumor tissues. Antagonists for GHRH inhibit the proliferation of a wide range of cancer cell lines in vitro and inhibit xenograft tumor growth, which demonstrates their potential clinical utility. 111 Similar to SRLs, GHRH antagonists inhibit endocrine secretion of GH from the anterior pituitary to varying extents. However, the main action of these antagonists is through direct inhibition of GHRH receptors in tumor tissues. Potential applications besides oncology include acromegaly, diabetic retinopathy, and nephropathy. 111
Pegvisomant is a chemically modified (PEGylated) analog of GH that was discovered in John Kopchick’s lab and developed by Pfizer. It is the only clinically approved GHR antagonist and has been approved by the FDA for the treatment of acromegaly [reviewed in ref. 6,114,115 ]. The first reported GHR antagonist was a bovine GH protein that was mutated with three amino acid substitutions located in helix 3, which resulted in a dwarf phenotype in transgenic mice. 6,116,117 A similar result was observed with a single amino acid substitution of glycine to arginine at position 120 on helix 3 of human GH (G120R). 118 Pegvisomant contains a G120K mutation (substitution to a lysine also allows PEGylation at this site). Eight more mutations (H18D, H21N, R167N, K168A, D171S, K172R, E174S, and I179T) were introduced at binding site 1 on the molecule to prevent PEGylation and to increase the affinity for the receptor at this site. 6 This antagonist, which is the protein component of pegvisomant, is known as B2036. The half-life of native GH (as well as B2036) in the circulation is short, which limits its in vivo efficacy. To reduce clearance and increase the serum half-life, polyethylene glycol-5000 (PEG5000) was conjugated to the molecule. 119 PEGylation extends the serum half-life, delays renal clearance, and reduces the immunogenicity of pegvisomant (B2036-PEG). B2036 competes with GH in vitro on the basis of an increased affinity for the GHR. However, PEGylation reduces the affinity for the receptor somewhat. Because pegvisomant targets the GHR instead of GH, it results in reduced IGF1 and enhanced GH levels through the negative-feedback loop. Therefore, measurement of GH is not useful to monitor treatment of acromegaly with pegvisomant: instead IGF1 is determined as a surrogate biomarker. 120,121 In addition, pegvisomant treatment decreases the insulin and glucose concentrations. 122
Pegvisomant is highly efficacious with only mild-side effects. One concern was potential adenoma growth caused by the increased levels of circulating GH. From the clinical trials conducted so far, changes in the tumor size or recurrence were infrequent, but further assessment needs to be carried out. An evaluation of pegvisomant as long-term monotherapy in acromegalic patients from the global safety surveillance study ACROSTUDY reported increases or increases/decreases in the tumor sizes in 12 of 542 subjects (2.2%). 7 Another study reviewed the efficacy of pegvisomant as a monotherapy for acromegaly over a 10-year period, and showed 6 of 64 (9.4%) cases with tumor growth. 123 Pegvisomant has also been evaluated in a combination therapy with SRL, particularly with respect to normalizing the IGF1 concentration in acromegalic patients who have failed SRL monotherapy. The outcome of a 42-week study of active acromegalic patients demonstrated that the combined therapy was effective in normalizing the levels of IGF1 and that there was no indication of tumor growth. 124 However, an analysis of 62 SRL-resistant acromegalic patients indicated better IGF1 normalization with pegvisomant monotherapy compared to combined pegvisomant/SRL treatment. 125 Although pegvisomant is well tolerated and highly effective, some limitations need to be considered. Pegvisomant is more costly than SRL, and daily injection is required. Treatment side-effects include elevated aminotransferase levels and injection site reactions (lipohypertrophy).
As described above, a small number of preclinical studies have demonstrated efficacy for pegvisomant in certain tumor models. 71,72,73,76 One obstacle to preclinical use in animal models is the species specificity of the drug. Both human GH and the protein component of pegvisomant (B2036) can bind the human and mouse GHR, but pegylation significantly reduces the affinity for the mouse GHR. Consequently, much higher concentrations of pegvisomant are necessary to reduce serum IGF1 in mice. 47 In addition, rodent GH does not activate the human or primate GHR, so the use of pegvisomant in animal models of disease does not address the effect of the blockade of systemic GH. Therefore, although early animal studies have been promising, these limitations combine to reduce the potential of these in vivo studies to support clinical translation.
Antagonist–GHBP fusion proteins
An alternative approach that is used to generate long-acting forms of protein therapeutics involves generating larger chimeric proteins that avoid kidney filtration. Richard Ross and colleagues from Asterion Ltd. have developed fusion proteins composed of the GH ligand or a GHR antagonist fused to GH-binding protein (GHBP), the extracellular domain of the GHR, which is proteolytically cleaved from the receptor and exists in the circulation (Fig. 4). The fusion of GH to its natural binding protein decreases its immunogenicity and prolongs its half-life in the circulation. 126 Initially, a GH–GHBP fusion protein agonist was generated for the treatment of GH deficiency. 127 This chimeric protein was found to exist in solution as both a monomer and a dimer. In the dimer form, the GH portion of one molecule bound to the receptor portion of another molecule in a head-to-tail reciprocal dimer. More recently Wilkinson et al. demonstrated that fusion of GHBP to a GHR antagonist protein similar to B2036 significantly reduced IGF1 by 14% after a single subcutaneous injection in rabbits and may be useful for treating acromegaly. 128 Introduction of a W104A mutation in the fused GHBP prevented intra- and inter-molecular binding. Three chimeric GHR antagonists were generated with extended in vivo clearance times the terminal half-life of the fusion proteins was greater than 20 h in rats. 128
Advances in antisense therapy have led to development of novel GHR antagonists (Fig. 4). Antisense oligonucleotides (ASOs) are short single-stranded DNA or RNA molecules (or chemical analogs) that bind and induce the degradation of target RNAs. 129 Early studies reported an inhibitory effect of GHR-targeted antisense oligonucleotides on GHR expression and IGF1 production in mice. 130,131 Antisense Therapeutics Ltd. is developing an antisense oligonucleotide drug, ATL1103 (now atesidorsen). Atesidorsen is a 20-mer ASO that has been modified to enhance its stability and circulating half-life. In Phase II outcomes, twice-weekly treatment with 200 mg atesidorsen was well tolerated and decreased the serum IGF1 concentration by 27.8% at week 14 and 18.7% at week 21 in acromegalic patients. 132 In addition, interim analysis from a small higher dose study using twice-weekly 300 mg atesidorsen for 13 weeks demonstrated results consistent with the Phase II trial outcomes (Antisense Therapeutic Ltd.).
GHR antibodies that inhibit GHR-mediated signal transduction have been reported. 133,134,135,136 Stuart Frank’s lab has developed an inhibitory conformation-sensitive monoclonal antibody (Anti-GHRcyt-mAb) that targets the extracellular domain of the rabbit GHR. Anti-GHRcyt-mAb effectively inhibits activation and downstream signal transduction of the rabbit and human GHR. 133,137 Similarly, Sun et al. 136 have reported a monoclonal antibody (GF185) that targets the human GHR, which acts as a full competitor for GH binding and also inhibits GHR signaling. Lan et al. 134 have generated an anti-idiotypic antibody (CG-86) which mimics an epitope on porcine GH and investigated the inhibitory effects on GH signaling and cell proliferation, which demonstrated the potential utility of this approach for generating GH antagonists. More recently Pfizer has reported development of a humanized GHR monoclonal antagonist antibody (RN172), which blocked GH signaling in vitro and reduced IGF1 production in monkeys following a single-intravenous injection. 135
The only small molecule GHR antagonist that has been reported is an orally available compound BVT-A (N-[5-(aminosulfonyl)-2-methylphenyl]-5-bromo-2-furamide). In two studies, BVT-A suppressed GH induction of IGF1 expression in hepatocytes in vitro and reduced GH stimulation of IGF1 secretion and body weight in hypophysectomized rats. 138,139 However, it is unclear where in the GH signaling pathway this compound acts, and no subsequent activity has been reported in this area since the original publication.
Inhibitors of GH signal transduction pathways (post-receptor)
Given that GH activates JAK-STAT, PI3K/AKT/mTOR and MAPK signaling, agents which target components of these signaling pathways would be expected to modulate pathway-specific GH effects. However, targeting GH signal transduction pathways will unlikely be specific to GH signaling because other receptors and cell signaling pathways can also utilize the same signaling pathways as GH. The potential for small molecules to inhibit these pathways and non-selectively inhibit GHR signaling needs to be considered in small molecule discovery studies. A detailed description of therapeutic drugs that target molecules in the GHR signal transduction pathways is beyond the scope of the current review, and we refer the reader to recent reviews. 140,141,142,143,144
Growth Hormone Deficiency and Type 2 Diabetes Risk
Besides widely discussed symptoms such as developmental abnormalities, fatigue, lack of memory, and mental health problems, growth hormone deficiency (GHD) may result in an increased risk of developing type 2 diabetes mellitus (T2DM), according to the results of a study.
A team led by researchers in Berchem, Belgium, argue that GHD is associated with obesity and visceral fat deposits which may raise patients’ risk of developing T2DM.
In the study, “Prevalence of diabetes mellitus in 6050 hypopituitary patients with adult-onset growth hormone (GH) deficiency before GH replacement - a KIMS analysis,” the researchers took a closer look at the connection between GHD and T2DM. The study was published online ahead of print in December 2012. It appears in the European Journal of Endocrinology.
The researchers looked at data on 6,050 patients with adult-onset, untreated GHD from KIMS (Pfizer International Metabolic Database). They performed Poisson-regression analyses to search for associations between the patients’ baseline characteristics and diabetes prevalence.
The prevalence of diabetes was positively associated with age, body mass index, waist circumference, number of pituitary deficiencies, and family history of diabetes, among other factors. The results of the study showed that the prevalence of diabetes among patients with GHD was 9.3%, compared to an expected 8.2%, derived from the patients’ baseline characteristics. The factors that were most likely to affect the difference between expected and observed diabetes prevalence proportions were patients’ age and their body mass indexes.
The researchers conclude that their study demonstrates an increased prevalence of diabetes among patients with growth hormone deficiency. They state that this association can be largely explained by adverse body compositions in people with GHD. According to the study authors, encouraging patients to adopt lifestyle modifications early on in disease progression may help them reduce a later risk of developing type 2 diabetes.
Can IGF Treat Diabetes?
That’s a question researchers are trying to answer. One clue may come from a medicine called mecasermin (Increlex). It’s a synthetic, or man-made, form of IGF. Doctors use it to treat kids who aren’t growing the way they should. Low blood sugar (hypoglycemia) is one side effect of the drug. IGF also lowered blood sugar in studies of adults with type 2 diabetes. Insulin resistance got much better in these patients. IGF plays many different roles in the body, so there’s still a lot to learn about how it works. Right now, IGF is approved only for growth problems in children.
Does Lack of Growth Hormone Prevent Diabetes and Cancer?
A 22-year study of an extended family in Ecuador suggests that insensitivity to human growth hormone, which causes a condition called Laron dwarfism, also has health benefits. Researchers found that none of the 100 affected people in the study suffered from diabetes and only one had a non-lethal case of cancer. In comparison, five percent of 1600 unaffected relatives studied over the same time period were diagnosed with diabetes and 17 percent with cancer, rates similar to those of the broader Ecuadorian population.
The disorder is caused by a mutation in the receptor for human growth hormone, which renders people with two copies insensitive to the hormone. Researchers hope the findings, published today in Science Translational Medicine, will aid in the development of new drugs to help combat or prevent some of the diseases of aging. Drugs that block human growth hormone are already on the market to treat a condition related to gigantism.
Growth hormone is a crucial protein produced by the pituitary that directs growth and cell division. While some people think that supplements of human growth hormone (HGH) can combat aging—Sylvester Stalone was caught with HGH in Australia several years ago–animal studies suggest the opposite mice without growth hormone live significantly longer and are protected against cancer, one of the most deadly diseases of aging.
As I noted in a previous story describing the project
“In the mouse, the effect is major and striking,” says Andrzej Bartke, a biologist at Southern Illinois University in Springfield, who is not involved in the project. “They seem protected from cancer and appear to have delayed aging by various measures. But there is almost no evidence that growth-hormone deficiency would extend life in humans.”
The new study, conducted by cell biologist Valter Longo of the University of Southern California and Ecuadorian endocrinologist Jaime Guevara-Aguirre, supports the animal research. According to a press release from the journal:
To pinpoint the molecular causes for this remarkable lack of disease, the researchers performed gene expression analyses of thousands of genes from blood samples of family members. They found that family members with the [growth hormone receptor] gene mutation have lower amounts of Insulin-like Growth Factor 1 or IGF-I, as well as lower insulin concentrations and higher insulin sensitivity. And when stressed, their cells tend to self-destruct rather than accumulate DNA damage. All of these features are known to promote longevity in lower organisms. Although it’s difficult to prove that major reductions in IGF-I and insulin concentrations are responsible for the lack of cancer and diabetes in this Ecuadorian family, the findings coincide with similar observations in lower organisms like yeast, worms and mice. In yeast, mutations in growth genes protect against age-related genomic havoc, while mutations in insulin-related signaling pathways increase life span and reduce abnormal cell proliferation in worms.
Drug companies are currently testing blockers of a molecule that acts downstream of IGF-1 as a treatment for cancer. If IGF-1 works, it’s not yet clear if the most effective intervention will be as a preventative measure, perhaps targeting families with a history of cancer, or if growth-hormone or IGF-1 depletion could be used as a cancer treatment. According to a press release from the university, Longo’s team would initially seek approval for a clinical trial to test HGH targeting drugs for the protection of patients undergoing chemotherapy.
The family in the study, identified in the 1990s, is centered in the Loja province in the southern portion of Ecuador, an isolated mountain region where intermarriage is common. The family descends from Spanish Jews thought to have emigrated after the Inquisition. (The mutation was originally identified in a small number of people in Israel.) People with the condition are small and obese, but little was known about their longevity.
According to the new study, people with the mutations don’t live longer. In fact, they are more likely to die from from substance abuse and accidents. In addition, people with the mutation suffer other health problems beyond short stature. As I noted in the previous story,
Children with the condition seem more susceptible to pneumonia and diarrhea, common scourges of poor rural communities, and they die at twice the rate of their unaffected siblings. Those who survive to adulthood typically have high cholesterol and triglycerides, risk factors for heart disease. Some die of heart disease, an uncommon occurrence in rural Ecuador, but preliminary reports suggest that Laron dwarves are protected from artherosclerosis, arterial hardening that can lead to heart attack. Adding to the puzzle is anecdotal evidence suggesting that they don’t get cancer or type 2 diabetes. “It’s a balance: if you turn down risk of cancer, you might turn up risk of heart disease,” says Steven N. Austad, a biologist at the University of Texas Health Sciences Center, in San Antonio, who is not involved in the project.