Despite higher body fat content, Ecuadorian subjects with Laron syndrome have less insulin resistance and lower incidence of diabetes than their relatives
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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Fasting and Fasting Mimicking Diets in Obesity and Cardiometabolic Disease Prevention and Treatment
2022, Physical Medicine and Rehabilitation Clinics of North AmericaCitation 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
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2022, Growth Hormone and IGF ResearchGrowth 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 ResearchCitation 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.
Assessing insulin sensitivity and resistance in syndromes of severe short stature
2020, Growth Hormone and IGF ResearchCitation 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.
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