Mechanisms of Insulin Action and Insulin Resistance

Physiological Reviews, Год журнала: 2018, Номер 98(4), С. 2133 - 2223

Опубликована: Авг. 1, 2018

The 1921 discovery of insulin was a Big Bang from which vast and expanding universe research into action resistance has issued. In the intervening century, some discoveries have matured, coalescing solid fertile ground for clinical application; others remain incompletely investigated scientifically controversial. Here, we attempt to synthesize this work guide further mechanistic investigation inform development novel therapies type 2 diabetes (T2D). rational such necessitates detailed knowledge one key pathophysiological processes involved in T2D: resistance. Understanding resistance, turn, requires normal action. review, both physiology pathophysiology are described, focusing on three target tissues: skeletal muscle, liver, white adipose tissue. We aim develop an integrated physiological perspective, placing intricate signaling effectors that carry out cell-autonomous response context tissue-specific functions generate coordinated organismal response. First, section II, effects direct, tissue reviewed, beginning at receptor working downstream. Section III considers critical underappreciated role crosstalk whole body action, especially essential interaction between lipolysis hepatic gluconeogenesis. is then described IV. Special attention given pathways become resistant setting chronic overnutrition, alternative explanation phenomenon ‟selective resistanceˮ presented. Sections V, VI, VII critically examine evidence against several putative mediators V reviews linking bioactive lipids diacylglycerol, ceramide, acylcarnitine resistance; VI impact nutrient stresses endoplasmic reticulum mitochondria discusses non-cell autonomous factors proposed induce including inflammatory mediators, branched-chain amino acids, adipokines, hepatokines. Finally, VIII, propose model links these final common metabolite-driven gluconeogenesis ectopic lipid accumulation.

Язык: Английский

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Pathophysiology of Type 2 Diabetes Mellitus

International Journal of Molecular Sciences, Год журнала: 2020, Номер 21(17), С. 6275 - 6275

Опубликована: Авг. 30, 2020

Type 2 Diabetes Mellitus (T2DM), one of the most common metabolic disorders, is caused by a combination two primary factors: defective insulin secretion pancreatic β-cells and inability insulin-sensitive tissues to respond appropriately insulin. Because release activity are essential processes for glucose homeostasis, molecular mechanisms involved in synthesis insulin, as well its detection tightly regulated. Defects any these can lead imbalance responsible development disease. This review analyzes key aspects T2DM, pathways implicated metabolism leading T2DM resistance. For that purpose, we summarize data gathered up until now, focusing especially on synthesis, release, sensing downstream effects individual organs. The also covers pathological conditions perpetuating such nutritional factors, physical activity, gut dysbiosis memory. Additionally, because associated with accelerated atherosclerosis development, here some link resistance (IR) cardiovascular risk important complications T2DM.

Язык: Английский

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Adipose Tissue Dysfunction as Determinant of Obesity-Associated Metabolic Complications

International Journal of Molecular Sciences, Год журнала: 2019, Номер 20(9), С. 2358 - 2358

Опубликована: Май 13, 2019

Obesity is a critical risk factor for the development of type 2 diabetes (T2D), and its prevalence rising worldwide. White adipose tissue (WAT) has crucial role in regulating systemic energy homeostasis. Adipose expands by combination an increase adipocyte size (hypertrophy) number (hyperplasia). The recruitment differentiation precursor cells subcutaneous (SAT), rather than merely inflating cells, would be protective from obesity-associated metabolic complications. In metabolically unhealthy obesity, storage capacity SAT, largest WAT depot, limited, further caloric overload leads to fat accumulation ectopic tissues (e.g., liver, skeletal muscle, heart) visceral depots, event commonly defined as "lipotoxicity." Excessive lipid local inflammation insulin resistance (IR). Indeed, overnutrition triggers uncontrolled inflammatory responses WAT, leading chronic low-grade inflammation, therefore fostering progression IR. This review summarizes current knowledge on dysfunction obesity associated abnormalities, such A better understanding mechanisms expansion required future therapeutic approaches

Язык: Английский

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The integrative biology of type 2 diabetes

Nature, Год журнала: 2019, Номер 576(7785), С. 51 - 60

Опубликована: Дек. 4, 2019

Язык: Английский

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Biochemical and cellular properties of insulin receptor signalling

Nature Reviews Molecular Cell Biology, Год журнала: 2017, Номер 19(1), С. 31 - 44

Опубликована: Окт. 4, 2017

Язык: Английский

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Polycystic Ovary Syndrome: Pathophysiology, Presentation, and Treatment With Emphasis on Adolescent Girls

Journal of the Endocrine Society, Год журнала: 2019, Номер 3(8), С. 1545 - 1573

Опубликована: Июнь 14, 2019

Abstract Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by hyperandrogenism and chronic anovulation. Depending on diagnostic criteria, 6% to 20% of reproductive aged women are affected. Symptoms PCOS arise during the early pubertal years. Both normal female development irregular menstrual cycles, anovulation, acne. Owing complicated interwoven pathophysiology, discerning inciting causes challenging. Most available clinical data communicate findings outcomes in adult women. Whereas Rotterdam criteria accepted for women, different adolescent girls have been delineated. Diagnostic features irregularity, hyperandrogenism, and/or hyperandrogenemia. Pelvic ultrasound not needed diagnosis girls. Even before definitive PCOS, adolescents with signs androgen excess oligomenorrhea/amenorrhea, can be regarded as being “at risk PCOS.” Management both those at confirmed includes education, healthy lifestyle interventions, therapeutic interventions targeting their symptoms. Interventions include metformin, combined oral contraceptive pills, spironolactone, local treatments hirsutism In addition ascertaining associated comorbidities, management should also regular follow-up visits planned transition care providers. Comprehensive knowledge regarding pathogenesis will enable earlier identification high propensity develop PCOS. Timely implementation individualized improve overall adolescence, prevent quality life.

Язык: Английский

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Fructose metabolism and metabolic disease

Journal of Clinical Investigation, Год журнала: 2018, Номер 128(2), С. 545 - 555

Опубликована: Янв. 31, 2018

Increased sugar consumption is increasingly considered to be a contributor the worldwide epidemics of obesity and diabetes their associated cardiometabolic risks. As result its unique metabolic properties, fructose component may particularly harmful. Diets high in can rapidly produce all key features syndrome. Here we review biology metabolism as well potential mechanisms by which excessive contribute disease.

Язык: Английский

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The aetiology and molecular landscape of insulin resistance

Nature Reviews Molecular Cell Biology, Год журнала: 2021, Номер 22(11), С. 751 - 771

Опубликована: Июль 20, 2021

Язык: Английский

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Inflammatory Links Between High Fat Diets and Diseases

Frontiers in Immunology, Год журнала: 2018, Номер 9

Опубликована: Ноя. 13, 2018

In recent years, chronic overnutrition, such as consumption of a high-fat diet (HFD), has been increasingly viewed significant modifiable risk factor for diseases diabetes and certain types cancer. However, the mechanisms by which HFDs exert adverse effects on human health remains poorly understood. Here, this paper will review scientific literature about HFD-induced inflammation subsequent development cancer, with an emphasis involved. Given expanding global epidemic excessive HFD intake, understanding impacts these medical conditions, gaining great insights into possible underlying mechanisms, developing effective therapeutic strategies are importance.

Язык: Английский

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The cell biology of systemic insulin function

The Journal of Cell Biology, Год журнала: 2018, Номер 217(7), С. 2273 - 2289

Опубликована: Апрель 5, 2018

Insulin is the paramount anabolic hormone, promoting carbon energy deposition in body. Its synthesis, quality control, delivery, and action are exquisitely regulated by highly orchestrated intracellular mechanisms different organs or “stations” of its bodily journey. In this Beyond Cell review, we focus on these five stages journey insulin through body captivating cell biology that underlies interaction with each organ. We first analyze insulin’s biosynthesis export from β-cells pancreas. Next, pass partial clearance liver temporality periodicity linked to secretion. Continuing journey, briefly describe blood vasculature still-debated exit capillary beds. Once parenchymal interstitium muscle adipose tissue, promotes glucose uptake into myofibers adipocytes, elaborate intricate signaling vesicle traffic underlie fundamental function. Finally, touch upon renal degradation end action. Cellular discernment availability should prove critical understanding pivotal physiological functions how their failure leads diabetes.

Язык: Английский

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