Despite higher body fat content, Ecuadorian subjects with Laron syndrome have less insulin resistance and lower incidence of diabetes than their relatives

doi:10.1016/j.ghir.2015.08.002

Growth Hormone & IGF Research

Volume 28, June 2016, Pages 76-78

https://doi.org/10.1016/j.ghir.2015.08.002 Get rights and content

Highlights

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Effects of the lack of a functional GHR in insulin sensitivity
•
Effect of the lack of a functional GHR on insulin secretion
•
Effect of the lack of a functional GHR on insulin resistance

Abstract

In the present pandemics of obesity and insulin resistant diabetes mellitus (DM), the specific contribution of etiological factors such as shifts in nutritional and exercise patterns, genetic and hormonal, is subject of ongoing research. Among the hormonal factors implicated, we selected obesity-driven insulin resistance for further evaluation. It is known that growth hormone (GH) has profound effects on carbohydrate metabolism. In consequence, we compared the effects of the lack of the counter-regulatory effects of GH, in a group of subjects with GH receptor deficiency (GHRD) due to a mutated GH receptor vs. that of their normal relatives. It was found that, despite their obesity, subjects with GHRD, have diminished incidence of diabetes, lower glucose and insulin concentrations, and lower values of indexes indicative of insulin resistance such as HOMA-IR. The GHRD subjects were also capable of appropriately handling glucose or mixed meal loads despite diminished insulin secretion. These observations allow us to suggest that the association of obesity with increased risk for diabetes appears to be dependent on intact growth hormone signaling.

Introduction

Worldwide change of nutritional patterns, especially a substantial increase in the consumption of carbohydrates and refined sugars, has consistently been associated to a dramatic increase in the frequency of obesity and comorbidities, including insulin-resistant diabetes [1]. As a result, society is facing today the largest obesity pandemics in history that is already affecting the economies of all nations and severely compromising their health systems. Identification of its causes and understanding of its mechanisms will lead to rational, scientifically-based design of public policy that is thereby urgently needed.

The genesis and development of obesity and associated metabolic abnormalities follows a sequence in which excess body fat accumulation is the initial derangement, followed by insulin resistance, pancreatic exhaustion and development of diabetes and other comorbidities [2]. In consequence, reduction of obesity frequency is the single most important public health measure to be implemented; nonetheless, ascertainment of the mechanisms underlying the transition from obesity to insulin resistance and then to diabetes, will allow one to determine what measures are the most adequate to control these abnormalities, but also to understand what influences have more specific importance in their sequence of appearance, in order to properly design strategies and approaches to deal with them more efficiently.

In the above context, we have focused on the effect of the growth hormone (GH) receptor and on the specific role that GH has on obesity and carbohydrate metabolism (CHO). Indeed, we recently reported the metabolic characteristics of the Ecuadorian cohort of subjects with Laron syndrome (LS) due to growth hormone receptor deficiency (GHRD) who despite having obesity and a high percentage of body fat (Fig. 1), display markedly increased insulin sensitivity compared with age- and BMI-matched control relatives, and have no instances of overt diabetes, which is present in 6% of unaffected relatives [3]. The unique feature of this group is the total absence of GH actions in the body, due to a mutated GHR incapable of transmitting the GH signal [4]. As a consequence of this peripheral insensitivity, the counter-regulatory effects of GH as well as its deleterious effects on carbohydrate metabolism should also be abolished or attenuated [5].

Section snippets

Effects of the lack of a functional GHR in insulin sensitivity

It has been previously shown that mice homozygous for a GHR deletion have increased adiposity, low serum concentrations of insulin and glucose, enhanced insulin sensitivity and increased adiponectin levels [6]. We recently reported that fasting insulin, 2-hour (h) serum glucose during an oral glucose tolerance test (OGTT), very low-density lipoprotein and triacylglycerol levels were all significantly lower in individuals with GHRD, which is indicative of insulin sensitivity. Indeed, the measure

Effect of the lack of a functional GHR on insulin secretion

Raising serum glucose leads to its increased uptake into pancreatic beta cells via the membranal glucose transporter GLUT2; thereafter, subsequent increased intracellular glucose induces ATP production with higher ATP/ADP ratio that induces closing of potassium channels, cell membrane depolarization, opening of calcium channels and insulin secretion [10]. Following this sequence, glucose induces a biphasic pattern of insulin release beginning with a first-phase that occurs within the first few

Effect of the lack of a functional GHR on insulin resistance

Insulin promotes the entry of glucose, amino acids and fatty acids into cells followed by generation of the energy necessary to perform physiological functions at different levels [19]. If insulin action is inefficient, defective, or strongly opposed, the most basic mechanisms necessary to support normal physiology are affected.

Physiological actions of insulin include proper glucose uptake in skeletal muscle, timely storage of glucose as glycogen, and suppression of glucose production by the

Summary

When compared with control relatives, subjects with GHRD have lower incidence of diabetes along with diminished insulin resistance, despite their obesity and increased percentage of body fat. Considering that the defective GHR generates a complete absence of the direct metabolic effects of GH, the most likely explanation for the dissociation of obesity and insulin resistance in these individuals is the lack of the counter-regulatory effects of GH. These observations allow us to suggest that the

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Insulin secretion and carbohydrate metabolism in patients with Laron syndrome: from hypoglycemia to diabetes mellitus

Cited by (17)

Fasting and Fasting Mimicking Diets in Obesity and Cardiometabolic Disease Prevention and Treatment
2022, Physical Medicine and Rehabilitation Clinics of North America
Citation Excerpt :
Laron syndrome is a genetic condition caused by a mutation in the growth hormone receptor (GHR) gene that leads to severe GHR and IGF-1 deficiencies. Individuals with GHR deficiency, despite being obese, rarely develop diabetes,128 in agreement with the insulin-sensitizing effects of GHRD in mice and humans.129,130 GHR deficient individuals have one-third of the serum insulin concentration than that of their relatives and are insulin sensitive with HOMA-IR of 0.34 for GHR deficient group but 0.96 for their relatives.128
Growth hormone modulates Trypanosoma cruzi infection in vitro
2022, Growth Hormone and IGF Research
Chagas disease (CD) is caused by the protozoan parasite, Trypanosoma cruzi. It affects 7 to 8 million people worldwide and leads to approximately 50,000 deaths per year. In vitro and in vivo studies had demonstrated that Trypanosoma cruziinfection causes an imbalance in the hypothalamic-pituitary-adrenal (HPA) axis that is accompanied by a progressive decrease in growth hormone (GH) and prolactin (PRL) production. In humans, inactivating mutations in the GH receptor gene cause Laron Syndrome (LS), an autosomal recessive disorder. Affected subjects are short, have increased adiposity, decreased insulin-like growth factor-I (IGFI), increased serum GH levels, are highly resistant to diabetes and cancer, and display slow cognitive decline. In addition, CD incidence in these individuals is diminished despite living in highly endemic areas. Consequently, we decided to investigate the in vitro effect of GH/IGF-I on T. cruzi infection.
We first treated the parasite and/or host cells with different peptide hormones including GH, IGFI, and PRL. Then, we treated cells using different combinations of GH/IGF-I attempting to mimic the GH/IGF-I serum levels observed in LS subjects.
We found that exogenous GH confers protection against T. cruzi infection. Moreover, this effect is mediated by GH and not IGFI. The combination of relatively high GH (50 ng/ml) and low IGF-I (20 ng/ml), mimicking the hormonal pattern seen in LS individuals, consistently decreased T. cruzi infection in vitro.
The combination of relatively high GH and low IGF-I serum levels in LS individuals may be an underlying condition providing partial protection against T. cruzi infection.
Growth hormone receptor deficiency in humans associates to obesity, increased body fat percentage, a healthy brain and a coordinated insulin sensitivity
2020, Growth Hormone and IGF Research
Citation Excerpt :
These mechanisms might explain some of the positive findings in their morbidity and mortality profile [14,15], as well as provide leads to understand the positive findings in brain structure and function. The use of the HOMA and other homeostatic minimal models for assessing insulin sensitivity and resistance in this syndrome could be questioned considering that these measures are derived from determinations of fasting glucose and insulin concentrations [16,17] and, there is a constitutive diminishment of circulating insulin already existing in GHRD [13,14]. Although, we have observed that the HOMA Index correlates reasonably well with the low diabetes prevalence in GHRD [12], this homeostatic minimal model assessment, could be imprecise when determining the real insulin sensitivity status in these individuals since they have low insulin secretion, as it occurs with other groups that display a similar secretory deficit.
We have shown that subjects with Laron syndrome (LS) due to growth hormone receptor deficiency (GHRD) and their relatives have comparable brain structure and function; moreover, the brain of individuals affected with GHRD appears like those of younger people. While the functionally absent growth hormone receptor and the diminished concentrations of the insulin-like growth factor-I have been associated to these findings, the role of the insulin-glucose axis is emerging as an unavoidable consideration when determining the aetiology of these observations. In consequence, we decided to search for the potential and discrete associations between the neurological findings and several parameters of carbohydrate metabolism that might exist in the subjects affected with GHRD.
Individuals affected with GHRD were compared to relative controls. Besides standard measures of anthropometry, body composition and brain characteristics, the elements of the carbohydrate metabolism (CHO), including glucose, insulin, triacylglycerol and the free insulin growth factor binding protein 1 (IGFBP1) concentrations were determined. In addition, the correlations existing between the parameters of CHO and brain characteristics were established.
Besides the phenotypical characteristics of GHRD subjects, including those of brain structure and function, enhanced insulin sensitivity, and other minor, we observed that the insulin-regulated IGFBP1 had a consistent negative correlation with the main elements of the carbohydrate metabolism only in the individuals affected with the disease, and not in their relatives.
When compared to their relatives, subjects with GHRD who lack the counter-regulatory effects of GH on the insulin axis, despite their increased risk factor profile due to obesity and increased body fat percentage, have a healthy and younger looking brain associated to an enhanced and coordinated insulin sensitivity. Furthermore, it was observed that in the GHRD subjects IGFBP1 negatively correlates, in a constant and systematic manner, with the main elements of the CHO metabolism. These observations suggest a direct relationship between an efficient insulin sensitivity and a healthy brain.
Assessing insulin sensitivity and resistance in syndromes of severe short stature
2020, Growth Hormone and IGF Research
Citation Excerpt :
The explanation resides in the fact that in the latter, the inherent absence of GH counter-regulation allows insulin to act very efficiently and instead of having a disturbed CHO metabolism because of low insulin secretion, affected subjects display a diminished incidence of clinical T2DM despite a pancreatic reserve that is reduced from their in utero life. In any case, the selection of an appropriate method for evaluating insulin sensitivity and resistance in the two syndromes is challenging, especially considering that while having normal fasting glucose during childhood, adolescence and early adulthood, they concomitantly have diminished insulin secretion across all ages [3,41]. It should be considered that the calculations to determine IR using clamp techniques view insulin secretion and IS as linear measurements within an expected normal range; however, consider insulin resistance as a hyperbolic relationship based on the estimated glucose disposal rate.
Individuals affected with two genetic syndromes identified in Ecuador have severe short stature and diminished insulin secretion, along with essentially different GH counterregulatory effects on insulin action, which leads to the appearance of opposing metabolic phenotypes. In the case of Laron syndrome, subjects have enhanced insulin sensitivity and diminished incidence of type 2 diabetes mellitus. In the other clinical entity, individuals have innate insulin resistance, a varying degree of carbohydrate metabolism disturbances, glucose intolerance, and eventually insulin-resistant diabetes mellitus. Since both groups have diminished insulin secretion, the standard homeostatic minimal models for assessment of insulin sensitivity and resistance were used to see if they could properly identify the metabolic status, especially considering that these methodologies are simple and non-invasive procedures.
Fasting insulin concentrations, fasting glucose/fasting insulin ratio and various minimal models were determined in individuals from the two syndromic cohorts, as well as in a control group made of first-degree normal relatives of the insulin-resistant phenotype subjects.
The metabolic characteristics of enhanced insulin sensitivity in one of the syndromes and innate insulin resistance in the other could not be properly ascertained by the selected methodology. Furthermore, results were confusing and even discrepant with the clinical findings.
The standard homeostatic minimal models could not properly identify or discriminate insulin sensitivity and resistance in subjects with inherently diminished secretion. It is thereby suggested that these models should be used with caution in clinical situations where reduced secretion of the metabolic peptide is found or suspected.
High growth hormone serum partially protects mice against Trypanosoma cruzi infection
2023, FEBS Open Bio
Secondary diabetes mellitus in acromegaly
2023, Endocrine

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Despite higher body fat content, Ecuadorian subjects with Laron syndrome have less insulin resistance and lower incidence of diabetes than their relatives

Highlights

Abstract

Introduction

Section snippets

Effects of the lack of a functional GHR in insulin sensitivity

Effect of the lack of a functional GHR on insulin secretion

Effect of the lack of a functional GHR on insulin resistance

Summary

Lancet

Metabolism

Trends Genet.

Metabolism

Br. J. Anaesth.

Am. J. Clin. Nutr.

Prog. Lipid Res.

Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis

JAMA

Recent advances in obesity: genetics and beyond

ISRN Endocrinol.

GH receptor deficiency in ecuadorian adults is associated with obesity and enhanced insulin sensitivity

J. Clin. Endocrinol. Metab.

Mutation creating a new splice site in the growth hormone receptor genes of 37 Ecuadorean patients with Laron syndrome

Hum. Mutat.

Endocrine parameters and phenotypes of GHR gene disrupted mouse

Endocr. Rev.

Insulin secretion and carbohydrate metabolism in patients with Laron syndrome: from hypoglycemia to diabetes mellitus