A basic requirement for all vertebrates is stability of the level of blood glucose. This is essential for brain function. Regardless of large fluctuations in physical activity and food intake, blood sugar levels are held within very narrow limits. The key to this is insulin, the secretion of which is closely regulated by circulating substrates of energy metabolism. Insulin signals food abundance and initiates uptake and storage of carbohydrates, fats and amino acids. Energy supply and stability of blood sugar levels postprandial is usually accorded to glucagon and the catecholamines, but the reduction in insulin signalling postprandial is almost certainly just as important. How does insulin influence our metabolism? What are the key events in its action?

1. A brief summary of effects on key metabolic pathways and enzymes.

Control of the key enzymes of metabolism can be divided into two classes:

1. Covalent modification of enzymes, usually by phosphorylation or dephosphorylation of serine, threonine or tyrosine residues.

2. Allosteric feedback and feed-forward regulation by metabolic intermediates.

Enzymes involved in metabolism can be either activated or inactivated by phosphorylation. Examples or this are glycogen phosphorylase and hormone-sensitive lipase which are activated when phosphorylated and glycogen synthetase and pyruvate dehydrogenase are inactivated through phosphorylation. The protein kinases that catalyze phosphorylation of these enzymes are subject to control through cyclic nucleotides (PKA and cyclic AMP), Ca++ and diacylglycerol (PKC) and PI(3,4,5P)P3 (PKB).

The extent of enzyme phosphorylation is controlled by the balance between protein kinases and protein phosphatases. The picture becomes extremely complex when one knows that protein kinases can activate protein phosphatases. This is clearly the case for the insulin-activation of pyruvate dehydrogenase and, therefore, crucial in insulin’s stimulation of hepatic lipid synthesis.

Hormone-sensitive lipase activity in fat cells is regulated largely through cAMP activation of protein kinase A (PKA). The cyclic nucleotide levels is controlled through the balance between hormone-regulated G-protein control of adenylate cyclase and breakdown of cAMP catalyzed by phosphodiesterase. Insulin regulates cAMP levels through its stimulatory effect on the esterase and reduction of cAMP levels.

Insulin and “Opposing” Hormones control Metabolism

Insulin is an anabolic hormone, causing cells to take up energy substrates at times of excess. Insulin action is countered by the catabolic hormones glucagon, adrenalin and noradrenalin, and growth hormone. These act primarily through cyclic AMP (cAMP) and protein kinase A.


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The islets of Langerhans
The pancreatic Islets of Langerhans are the sites of production of insulin, glucagon and somatostatin. The figure below shows an immunofluorescence image in which antibodies specific for these hormones have been coupled to differing fluorescence markers. We can therefore identify those cells that produce each of these three peptide hormones. You can see that most of the tissue, around 80 %, is comprised of the insulin-secreting red-colored beta cells (ß-cells). The green cells are the α-cells (alpha cells) which produce glucagon. We see also some blue cells; these are the somatostatin secreting γ-cells (gamma cells). Note that all of these differing cells are in close proximity with one another. While they primarily produce hormones to be circulated in blood (endocrine effects), they also have marked paracrine effects. That is, the secretion products of each cell type exert actions on adjacent cells within the Islet.

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As I have already mentioned, the pancreas contains clusters of cells known as the Islets of Langerhans. They contain three cell types: alpha cells that produce glucagon, beta cells that produce insulin, and delta cells where somatostatin is synthesized. Together, these cells and their hormone products are responsible for the minute-to-minute regulation of metabolism. Metabolism in this case includes storage and release of carbohydrates and lipids, rates of energy production, protein synthesis and even the regulation of hunger. Seemingly minor aberrations in function of these cells have large and often devastating effects on an individual’s health.

Insulin secretion is stimulated by glucose, some amino acids and fatty acids. Let us take these up individually.

Monitoring Blood Glucose.
The basic functions and physiology of the beta cell are relatively well understood. A model of the beta cell showing the basic components for insulin secretion is presented below. A glucose “sensor” mechanism, a metabolic coupling to potassium channels to control plasma membrane potential and a voltage dependent Ca++ channel are required to link blood glucose levels to insulin secretion. Insulin containing granules are found in a reserve pool and a “readily released” pool.

Let us look at the “glucose sensor” system first. The beta cell’s primary function is to correlate release of insulin with changes in blood glucose concentration. Obviously, these cells must have a sensitive glucose-measuring device. Nature has achieved this by equipping the beta cell with a glucose transport protein (GLUT2) and a kinase (glucokinase) both of which have low affinities for glucose. GLUT2 is quite active, but the Km for glucose is around 5 mmol/l. Therefore, transport of glucose into the beta cell is rapid, but only when the blood glucose concentration exceeds post-meal levels.

Clinical Chemistry 54: 256-263, 2008.

Mechanisms of insulin secretion in pancreatic beta-cells.
Increase in ATP:ADP ratio inhibits the KATP channel, resulting in closure of the channel, depolarization of the membrane, influx of calcium, and release of insulin. Insulin secretion is stimulated by glucose oxidation via GK and by leucine stimulation of glutamate oxidation via GDH. Abnormally increased pyruvate levels in the beta-cell will stimulate insulin secretion. GLUT2, glucose transporter 2.

Background: Hypoglycemia in infants and children can lead to seizures, developmental delay, and permanent brain damage. Hyperinsulinism (HI) is the most common cause of both transient and permanent disorders of hypoglycemia. HI is characterized by dysregulated insulin secretion, which results in persistent mild to severe hypoglycemia. The various forms of HI represent a group of clinically, genetically, and morphologically heterogeneous disorders.

Content: Congenital hyperinsulinism is associated with mutations of SUR-1 and Kir6.2, glucokinase, glutamate dehydrogenase, short-chain 3-hydroxyacyl-CoA dehydrogenase, and ectopic expression on beta-cell plasma membrane of SLC16A1. Hyperinsulinism can be associated with perinatal stress such as birth asphyxia, maternal toxemia, prematurity, or intrauterine growth retardation, resulting in prolonged neonatal hypoglycemia. Mimickers of hyperinsulinism include neonatal panhypopituitarism, drug-induced hypoglycemia, insulinoma, antiinsulin and insulin-receptor stimulating antibodies, Beckwith-Wiedemann Syndrome, and congenital disorders of glycosylation. Laboratory testing for hyperinsulinism may include quantification of blood glucose, plasma insulin, plasma beta-hydroxybutyrate, plasma fatty acids, plasma ammonia, plasma acylcarnitine profile, and urine organic acids. Genetic testing is available through commercial laboratories for genes known to be associated with hyperinsulinism. Acute insulin response (AIR) tests are useful in phenotypic characterization. Imaging and histologic tools are also available for diagnosing and classifying hyperinsulinism. The goal of treatment in infants with hyperinsulinism is to prevent brain damage from hypoglycemia by maintaining plasma glucose levels above 700 mg/L (70 mg/dL) through pharmacologic or surgical therapy.

Summary: The management of hyperinsulinism requires a multidisciplinary approach that includes pediatric endocrinologists, radiologists, surgeons, and pathologists who are trained in diagnosing, identifying, and treating hyperinsulinism.

Diabetes 56:1489-1501, 2007

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Diabetes for All, An Introduction to Metabolism and Diabetes

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Recent Progress in Hormone Research 59:267-285 (2004)

There is now considerable consensus that the adipocyte hormone leptin and the pancreatic hormone insulin are important regulators of food intake and energy balance. Leptin and insulin fulfill many of the requirements to be putative adiposity signals to the brain. Plasma leptin and insulin levels are positively correlated with body weight and with adipose mass in particular. Furthermore, both leptin and insulin enter the brain from the plasma. The brain expresses both insulin and leptin receptors in areas important in the control of food intake and energy balance. Consistent with their roles as adiposity signals, exogenous leptin and insulin both reduce food intake when administered locally into the brain in a number of species under different experimental paradigms. Additionally, central administration of insulin antibodies increases food intake and body weight. Recent studies have demonstrated that both insulin and leptin have additive effects when administered simultaneously. Finally, we recently have demonstrated that leptin and insulin share downstream neuropeptide signaling pathways. Hence, insulin and leptin provide important negative feedback signals to the central nervous system, proportional to peripheral energy stores and coupled with catabolic circuits.