The insulin-like growth factor family of ligands (IGF-I, IGF-II, and insulin), receptors (IGF-IR, M6P/IGF-IIR, and insulin receptor [IR]), and IGF-binding proteins (IGFBP-1-6) play critical roles in normal human physiology and disease states. Insulin and insulin receptors are the focus of other chapters in this series and will therefore not be discussed further. Here we review the basic components of the IGF system, their role in normal physiology and in critical pathology's. While this review concentrates on the role of IGFs in human physiology, animal models have been essential in providing understanding of the IGF system, and its regulation, and are briefly described. IGF-I has effects via the circulation and locally within tissues to regulate cellular growth, differentiation, and survival, thereby controlling overall body growth. IGF-II levels are highest prenatally when it has important effects on growth. In adults, IGF-II plays important tissue-specific roles, including the maintenance of stem cell populations. Although the IGF-IR is closely related to the IR it has distinct physiological roles both on the cell surface and in the nucleus. The M6P/IGF-IIR, in contrast, is distinct and acts as a scavenger by mediating internalization and degradation of IGF-II. The IGFBPs bind IGF-I and IGF-II in the circulation to prolong their half-lives and modulate tissue access, thereby controlling IGF function. IGFBPs also have IGF ligand-independent cell effects.

Insulin-like growth factors (IGFs) are fundamental cell regulators with an evolutionary conserved role synchronising tissue growth, development and function according to metabolic conditions. Although structurally very similar to insulin, the IGFs act in a very different way as cell regulators. Whereas insulin is stored in a specific gland and released when needed, the IGFs are stored outside of cells with soluble binding proteins. A very complex system of six IGF binding proteins, each of which exists in various modified states and interacts with other proteins, provides a sophisticated system for conferring specificity to provide a finely tuned system for local regulation at the tissue level.

When originally discovered, one of the initial observations was that, when all of the insulin peptide was depleted from serum, the vast majority of the insulin activity remained and this was due to a single additional peptide, IGF-II. The IGF-II gene is adjacent to the insulin gene, which is a result of gene duplication, but has evolved to be considerably more complicated. It was one of the first genes recognised to be imprinted and expressed in a parent-of-origin specific manner. The gene codes for IGF-II mRNA, but, in addition, also codes for antisense RNA, long non-coding RNA, and several micro RNA. Recent evidence suggests that each of these have important independent roles in metabolic regulation. It has also become clear that an alternatively spliced form of the insulin receptor may be the principle IGF-II receptor. These recent discoveries have important implications for metabolic disorders and also for cancer, for which there is renewed acknowledgement of the importance of metabolic reprogramming.

Slowing eating rate appears to be an effective strategy for reducing food intake. This feasibility study investigated the effect of eating rate on post-meal responses using functional magnetic resonance imaging (fMRI), plasma gastrointestinal hormone concentrations, appetite ratings, memory for recent eating, and snack consumption. Twenty-one participants (mean age 23 years with healthy body mass index) were randomly assigned to consume a 600 kcal meal at either a “normal” or “slow” rate (6 vs. 24 min). Immediately afterwards, participants rated meal enjoyment and satisfaction. FMRI was performed 2-h post-meal during a memory task about the meal. Appetite, peptide YY, and ghrelin were measured at baseline and every 30 min for 3 h. Participants were given an ad-libitum snack three hours post-meal. Results were reported as effect sizes (Cohen’s d) due to the feasibility sample size. The normal rate group found the meal more enjoyable (effect size = 0.5) and satisfying (effect size = 0.6). Two hours post-meal, the slow rate group reported greater fullness (effect size = 0.7) and more accurate portion size memory (effect sizes = 0.4), with a linear relationship between time taken to make portion size decisions and the BOLD response in satiety and reward brain regions. Ghrelin suppression post-meal was greater in the slow rate group (effect size = 0.8). Three hours post-meal, the slow rate group consumed on average 25% less energy from snacks (effect size = 0.5). These data offer novel insights about mechanisms underlying how eating rate affects food intake and have implications for the design of effective weight-management interventions.

The pandemic of COVID-19, caused by the coronavirus, SARS-CoV-2, has had a global impact not seen for an infectious disease for over a century. This acute pandemic has spread from the East and has been overlaid onto a slow pandemic of metabolic diseases of obesity and diabetes consequent from the increasing adoption of a Western-lifestyle characterized by excess calorie consumption with limited physical activity. It has become clear that these conditions predispose individuals to a more severe COVID-19 with increased morbidity and mortality. There are many features of diabetes and obesity that may accentuate the clinical response to SARS-CoV-2 infection: including an impaired immune response, an atherothrombotic state, accumulation of advanced glycation end products and a chronic inflammatory state. These could prime an exaggerated cytokine response to viral infection, predisposing to the cytokine storm that triggers progression to septic shock, acute respiratory distress syndrome, and multi-organ failure. Infection leads to an inflammatory response and tissue damage resulting in increased metabolic activity and an associated increase in the mechanisms by which cells ingest and degrade tissue debris and foreign materials. It is becoming clear that viruses have acquired an ability to exploit these mechanisms to invade cells and facilitate their own life-cycle. In obesity and diabetes these mechanisms are chronically activated due to the deteriorating metabolic state and this may provide an increased opportunity for a more profound and sustained viral infection.