International Journal of Molecular Sciences

Editorial

Jump to: Research, Review

3 pages, 198 KiB

Open AccessEditorial

The Multiple Functions of Insulin Put into Perspective: From Growth to Metabolism, and from Well-Being to Disease

by Maria Elisabeth Street, Paolo Moghetti and Francesco Chiarelli

Int. J. Mol. Sci. 2023, 24(1), 200; https://doi.org/10.3390/ijms24010200 - 22 Dec 2022

Viewed by 908

Abstract

Insulin has pleiotropic effects, and is of importance both as a key regulator of glucose metabolism and as a growth factor [...] Full article

(This article belongs to the Special Issue Insulin Sensitivity/Resistance: From Physiology to Disease)

Research

Jump to: Editorial, Review

14 pages, 2052 KiB

Open AccessArticle

Plasma Metabolomics Profile of “Insulin Sensitive” Male Hypogonadism after Testosterone Replacement Therapy

by Lello Zolla and Marcello Ceci

Int. J. Mol. Sci. 2022, 23(3), 1916; https://doi.org/10.3390/ijms23031916 - 8 Feb 2022

Cited by 4 | Viewed by 2147

Abstract

Male hypogonadism is a disorder characterized by low levels of testosterone, but patients can either show normal insulin (insulin-sensitive (IS)) or over time they can become insulin-resistant (IR). Since the two groups showed different altered metabolisms, testosterone replacement therapy (TRT) could achieve different [...] Read more.

Male hypogonadism is a disorder characterized by low levels of testosterone, but patients can either show normal insulin (insulin-sensitive (IS)) or over time they can become insulin-resistant (IR). Since the two groups showed different altered metabolisms, testosterone replacement therapy (TRT) could achieve different results. In this paper, we analyzed plasma from 20 IS patients with low testosterone (<8 nmol/L) and HOMAi < 2.5. The samples, pre- and post-treatment with testosterone for 60 days, were analyzed by UHPLC and mass spectrometry. Glycolysis was significantly upregulated, suggesting an improved glucose utilization. Conversely, the pentose phosphate pathway was reduced, while the Krebs cycle was not used. Branched amino acids and carnosine metabolism were positively influenced, while β-oxidation of fatty acids (FFA) was not activated. Cholesterol, HDL, and lipid metabolism did not show any improvements at 60 days but did so later in the experimental period. Finally, both malate and glycerol shuttle were reduced. As a result, both NADH and ATP were significantly lower. Interestingly, a significant production of lactate was observed, which induced the activation of the Cori cycle between the liver and muscles, which became the main source of energy for these patients without involving alanine. Thus, the treatment must be integrated with chemicals which are not restored in order to reactivate energy production. Full article

(This article belongs to the Special Issue Insulin Sensitivity/Resistance: From Physiology to Disease)

► Show Figures

Figure 1

14 pages, 2782 KiB

Open AccessArticle

β Cell GHS-R Regulates Insulin Secretion and Sensitivity

by Geetali Pradhan, Chia-Shan Wu, Daniel Villarreal, Jong Han Lee, Hye Won Han, Akhilesh Gaharwar, Yanan Tian, Wenxian Fu, Shaodong Guo, Roy G. Smith and Yuxiang Sun

Int. J. Mol. Sci. 2021, 22(8), 3950; https://doi.org/10.3390/ijms22083950 - 11 Apr 2021

Cited by 11 | Viewed by 3155

Abstract

Growth hormone secretagogue receptor (GHS-R) is widely known to regulate food intake and adiposity, but its role in glucose homeostasis is unclear. In this study, we investigated the expression of GHS-R in mouse pancreatic islets and its role in glycemic regulation. We used [...] Read more.

Growth hormone secretagogue receptor (GHS-R) is widely known to regulate food intake and adiposity, but its role in glucose homeostasis is unclear. In this study, we investigated the expression of GHS-R in mouse pancreatic islets and its role in glycemic regulation. We used Ghsr-IRES-tauGFP mice, with Green Fluorescent Protein (GFP) as a surrogate for GHS-R, to demonstrate the GFP co-localization with insulin and glucagon expression in pancreatic islets, confirming GHS-R expression in β and α cells. We then generated β-cell-specific GHSR-deleted mice with MIP-Cre/ERT and validated that GHS-R suppression was restricted to the pancreatic islets. MIP-Cre/ERT;Ghsr^f/f mice showed normal energy homeostasis with similar body weight, body composition, and indirect calorimetry profile. Interestingly, MIP-Cre/ERT;Ghsr^f/f mice exhibited an impressive phenotype in glucose homeostasis. Compared to controls, MIP-Cre/ERT;Ghsr^f/f mice showed lower fasting blood glucose and insulin; reduced first-phase insulin secretion during a glucose tolerance test (GTT) and glucose-stimulated insulin secretion (GSIS) test in vivo. The isolated pancreatic islets of MIP-Cre/ERT;Ghsr^f/f mice also showed reduced insulin secretion during GSIS ex vivo. Further, MIP-Cre/ERT;Ghsr^f/f mice exhibited improved insulin sensitivity during insulin tolerance tests (ITT). Overall, our results confirmed GHS-R expression in pancreatic β and α cells; GHS-R cell-autonomously regulated GSIS and modulated systemic insulin sensitivity. In conclusion, β cell GHS-R was an important regulator of glucose homeostasis, and GHS-R antagonists may have therapeutic potential for Type 2 Diabetes. Full article

(This article belongs to the Special Issue Insulin Sensitivity/Resistance: From Physiology to Disease)

► Show Figures

Figure 1

Review

Jump to: Editorial, Research

13 pages, 624 KiB

Open AccessReview

Hypertension in Patients with Insulin Resistance: Etiopathogenesis and Management in Children

by Veronica Maria Tagi, Francesca Mainieri and Francesco Chiarelli

Int. J. Mol. Sci. 2022, 23(10), 5814; https://doi.org/10.3390/ijms23105814 - 22 May 2022

Cited by 13 | Viewed by 2664

Abstract

Insulin resistance (IR) is a key component in the etiopathogenesis of hypertension (HS) in patients with diabetes mellitus (DM). Several pathways have been found to be involved in this mechanism in recent literature. For the above-mentioned reasons, treatment of HS should be specifically [...] Read more.

Insulin resistance (IR) is a key component in the etiopathogenesis of hypertension (HS) in patients with diabetes mellitus (DM). Several pathways have been found to be involved in this mechanism in recent literature. For the above-mentioned reasons, treatment of HS should be specifically addressed in patients affected by DM. Two relevant recently published guidelines have stressed this concept, giving specific advice in the treatment of HS in children belonging to this group: the European Society of HS guidelines for the management of high blood pressure in children and adolescents and the American Academy of Pediatrics Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents. Our aim is to summarize the main pathophysiological mechanisms through which IR causes HS and to highlight the specific principles of treatment of HS for children with DM. Full article

(This article belongs to the Special Issue Insulin Sensitivity/Resistance: From Physiology to Disease)

► Show Figures

Figure 1

24 pages, 1138 KiB

Open AccessReview

Mechanisms by Which Skeletal Muscle Myokines Ameliorate Insulin Resistance

by Rekha Balakrishnan and Debbie C. Thurmond

Int. J. Mol. Sci. 2022, 23(9), 4636; https://doi.org/10.3390/ijms23094636 - 22 Apr 2022

Cited by 24 | Viewed by 8130

Abstract

The skeletal muscle is the largest organ in the body and secretes circulating factors, including myokines, which are involved in various cellular signaling processes. Skeletal muscle is vital for metabolism and physiology and plays a crucial role in insulin-mediated glucose disposal. Myokines have [...] Read more.

The skeletal muscle is the largest organ in the body and secretes circulating factors, including myokines, which are involved in various cellular signaling processes. Skeletal muscle is vital for metabolism and physiology and plays a crucial role in insulin-mediated glucose disposal. Myokines have autocrine, paracrine, and endocrine functions, serving as critical regulators of myogenic differentiation, fiber-type switching, and maintaining muscle mass. Myokines have profound effects on energy metabolism and inflammation, contributing to the pathophysiology of type 2 diabetes (T2D) and other metabolic diseases. Myokines have been shown to increase insulin sensitivity, thereby improving glucose disposal and regulating glucose and lipid metabolism. Many myokines have now been identified, and research on myokine signaling mechanisms and functions is rapidly emerging. This review summarizes the current state of the field regarding the role of myokines in tissue cross-talk, including their molecular mechanisms, and their potential as therapeutic targets for T2D. Full article

(This article belongs to the Special Issue Insulin Sensitivity/Resistance: From Physiology to Disease)

► Show Figures

Figure 1

12 pages, 557 KiB

Open AccessReview

Physiologic Insulin Resensitization as a Treatment Modality for Insulin Resistance Pathophysiology

by Frank Greenway, Brian Loveridge, Richard M. Grimes, Tori R. Tucker, Michael Alexander, Scott A. Hepford, Justin Fontenot, Candi Nobles-James, Carol Wilson, Adam M. Starr, Mohammed Abdelsaid, Stanley T. Lewis and Jonathan R. T. Lakey

Int. J. Mol. Sci. 2022, 23(3), 1884; https://doi.org/10.3390/ijms23031884 - 8 Feb 2022

Cited by 6 | Viewed by 5448

Abstract

Prevalence of type 2 diabetes increased from 2.5% of the US population in 1990 to 10.5% in 2018. This creates a major public health problem, due to increases in long-term complications of diabetes, including neuropathy, retinopathy, nephropathy, skin ulcers, amputations, and atherosclerotic cardiovascular [...] Read more.

Prevalence of type 2 diabetes increased from 2.5% of the US population in 1990 to 10.5% in 2018. This creates a major public health problem, due to increases in long-term complications of diabetes, including neuropathy, retinopathy, nephropathy, skin ulcers, amputations, and atherosclerotic cardiovascular disease. In this review, we evaluated the scientific basis that supports the use of physiologic insulin resensitization. Insulin resistance is the primary cause of type 2 diabetes. Insulin resistance leads to increasing insulin secretion, leading to beta-cell exhaustion or burnout. This triggers a cascade leading to islet cell destruction and the long-term complications of type 2 diabetes. Concurrent with insulin resistance, the regular bursts of insulin from the pancreas become irregular. This has been treated by the precise administration of insulin more physiologically. There is consistent evidence that this treatment modality can reverse the diabetes-associated complications of neuropathy, diabetic ulcers, nephropathy, and retinopathy, and that it lowers HbA1c. In conclusion, physiologic insulin resensitization has a persuasive scientific basis, significant treatment potential, and likely cost benefits. Full article

(This article belongs to the Special Issue Insulin Sensitivity/Resistance: From Physiology to Disease)

► Show Figures

Figure 1

17 pages, 915 KiB

Open AccessReview

Metformin and Insulin Resistance: A Review of the Underlying Mechanisms behind Changes in GLUT4-Mediated Glucose Transport

by Rok Herman, Nika Aleksandra Kravos, Mojca Jensterle, Andrej Janež and Vita Dolžan

Int. J. Mol. Sci. 2022, 23(3), 1264; https://doi.org/10.3390/ijms23031264 - 23 Jan 2022

Cited by 68 | Viewed by 11273

Abstract

Metformin is the most commonly used treatment to increase insulin sensitivity in insulin-resistant (IR) conditions such as diabetes, prediabetes, polycystic ovary syndrome, and obesity. There is a well-documented correlation between glucose transporter 4 (GLUT4) expression and the level of IR. Therefore, the observed [...] Read more.

Metformin is the most commonly used treatment to increase insulin sensitivity in insulin-resistant (IR) conditions such as diabetes, prediabetes, polycystic ovary syndrome, and obesity. There is a well-documented correlation between glucose transporter 4 (GLUT4) expression and the level of IR. Therefore, the observed increase in peripheral glucose utilization after metformin treatment most likely comes from the induction of GLUT4 expression and its increased translocation to the plasma membrane. However, the mechanisms behind this effect and the critical metformin targets are still largely undefined. The present review explores the evidence for the crucial role of changes in the expression and activation of insulin signaling pathway mediators, AMPK, several GLUT4 translocation mediators, and the effect of posttranscriptional modifications based on previously published preclinical and clinical models of metformin’s mode of action in animal and human studies. Our aim is to provide a comprehensive review of the studies in this field in order to shed some light on the complex interactions between metformin action, GLUT4 expression, GLUT4 translocation, and the observed increase in peripheral insulin sensitivity. Full article

(This article belongs to the Special Issue Insulin Sensitivity/Resistance: From Physiology to Disease)

► Show Figures

Figure 1

25 pages, 19003 KiB

Open AccessReview

Hyperinsulinemia and Its Pivotal Role in Aging, Obesity, Type 2 Diabetes, Cardiovascular Disease and Cancer

by Joseph A. M. J. L. Janssen

Int. J. Mol. Sci. 2021, 22(15), 7797; https://doi.org/10.3390/ijms22157797 - 21 Jul 2021

Cited by 87 | Viewed by 27529

Abstract

For many years, the dogma has been that insulin resistance precedes the development of hyperinsulinemia. However, recent data suggest a reverse order and place hyperinsulinemia mechanistically upstream of insulin resistance. Genetic background, consumption of the “modern” Western diet and over-nutrition may increase insulin [...] Read more.

For many years, the dogma has been that insulin resistance precedes the development of hyperinsulinemia. However, recent data suggest a reverse order and place hyperinsulinemia mechanistically upstream of insulin resistance. Genetic background, consumption of the “modern” Western diet and over-nutrition may increase insulin secretion, decrease insulin pulses and/or reduce hepatic insulin clearance, thereby causing hyperinsulinemia. Hyperinsulinemia disturbs the balance of the insulin–GH–IGF axis and shifts the insulin : GH ratio towards insulin and away from GH. This insulin–GH shift promotes energy storage and lipid synthesis and hinders lipid breakdown, resulting in obesity due to higher fat accumulation and lower energy expenditure. Hyperinsulinemia is an important etiological factor in the development of metabolic syndrome, type 2 diabetes, cardiovascular disease, cancer and premature mortality. It has been further hypothesized that nutritionally driven insulin exposure controls the rate of mammalian aging. Interventions that normalize/reduce plasma insulin concentrations might play a key role in the prevention and treatment of age-related decline, obesity, type 2 diabetes, cardiovascular disease and cancer. Caloric restriction, increasing hepatic insulin clearance and maximizing insulin sensitivity are at present the three main strategies available for managing hyperinsulinemia. This may slow down age-related physiological decline and prevent age-related diseases. Drugs that reduce insulin (hyper) secretion, normalize pulsatile insulin secretion and/or increase hepatic insulin clearance may also have the potential to prevent or delay the progression of hyperinsulinemia-mediated diseases. Future research should focus on new strategies to minimize hyperinsulinemia at an early stage, aiming at successfully preventing and treating hyperinsulinemia-mediated diseases. Full article

(This article belongs to the Special Issue Insulin Sensitivity/Resistance: From Physiology to Disease)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Insulin Sensitivity/Resistance: From Physiology to Disease

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (8 papers)

Editorial

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI