Physiological insulin secretion
المؤلف:
Holt, Richard IG, and Allan Flyvbjerg
المصدر:
Textbook of diabetes (2024)
الجزء والصفحة:
6th ed , page 225-227
2025-11-27
33
Insulin is secreted from the β cells of the pancreas. The insulin- producing cells are embedded in ~3 million islets of Langerhans scattered throughout the exocrine pancreatic tissue, where they account for up to 60% of the entire islet cell population. The total β- cell weight of a normal- weight adult does not exceed 1 g. This minute β- cell mass contains sufficient insulin to ensure up to 8–10 days of hormone requirement. Insulin is key for keeping daily plasma glucose concentration within a tight range in spite of wide fluctuations in carbohydrate intake (i.e. food ingestion) and demand (e.g. resting conditions vs physical activity). This implies tightly regulated, dynamic, and rapidly acting feedback between insulin secretion and plasma glucose concentration.
Glucose is actively transported inside the β cell in a linear manner with plasma glucose levels through the activity of glucose transporter 2 (GLUT 2). Once inside the cell, glucose is promptly phosphorylated by glucokinase, allowing its entry into the glycolytic pathway ending with the generation of adenosine triphosphate (ATP), the main driver of glucose- induced insulin secretion. Increased cytosolic ATP levels cause the closure of ATP- sensitive K+ channels and depolarization of the plasma membrane, causing the opening of the voltage- dependent Ca2+ channels and Ca2+ influx. The rise in intracellular Ca2+ concentration triggers the exocytosis of insulin granules and the release of insulin (Figure 1). Therefore, glucokinase is the rate- limiting step for the glycolytic flux and represents the main glucose sensor in the β cell, although recent experimental work has suggested the existence of additional sensing systems, including heterodimers of sweet taste receptors.
Fig1. Mechanisms of nutrient stimulus–secretion coupling in the pancreatic β cell. ATP, adenosine triphosphate; cMDH, cytoplasmic malate dehydrogenase; CoA, coenzyme A; DAG, diacylglycerol; GDH, glutamate dehydrogenase; GL, glycerolipid; GLUT1, glucose transporter 1; GPR, G- protein–coupled receptor; LC- CoA, long- chain fatty acids acyl coenzyme A esters; NEFA, non- esterified fatty acids; PC, pyruvate carboxylase; PKC, protein kinase C; TCA, tricarboxylic acid. Source: Newsholme et al. 2014.
Insulin secretion in response to glucose is biphasic in nature, with a short- lasting (a few minutes) first- phase increase in insulin secretion followed by a more sustained second- phase increase, which lasts as long as glucose levels remain elevated. The biphasic response of insulin secretion reflects the dynamics of spatially and functionally distinct intracellular insulin granule pools. According to this view, first- phase insulin secretion reflects fusion to the cell membrane of pre- docked granules from a readily releasable granule pool. This pool accounts for no more than 5% of the total granules in the cell. The increase in ATP concentration in the β cell on exposure to glucose facilitates movement of insulin granules and priming of exocytosis. The second phase of insulin secretion involves the recruitment of granules from a more distant and larger reserve pool as well as stimulation of de novo insulin synthesis [10]. This characteristic biphasic response of the β cell can be clearly appreciated using the hyperglycaemic clamp technique depicted in Figure 2. A square wave of hyperglycaemia is obtained with this technique, which distinguishes the first phase of insulin secretion, which is generally dependent on the magnitude of the early increase in glucose levels, and the second phase. Although such a clear- cut distinction is not fully apparent with a more gradual glucose increase, the same sequence – that is, an early insulin response followed by a more sustained response – occurs after the ingestion of carbohydrates or a regular meal.
Fig2. First- and second- phase plasma insulin response during hyperglycaemic clamp in healthy individuals. Plasma glucose is acutely raised +125 mg/dl (6.9 mmol/l) above baseline and maintained for the ensuing two hours. Plasma insulin concentration is measured at regular intervals. Source: DeFronzo et al. 1979 . Reproduced with permission of the American Physiological Society.
Insulin is secreted into the portal vein and exerts an immediate biological action on the liver. In the fasting state, portal insulin limits the supply of glucose from the liver into the systemic circulation to match the need of glucose- dependent tissues, primarily the central and peripheral nervous system and red blood cells. Basal insulin secretion is characterized by rapid oscillations with a 3–4- minute frequency. In the absorptive state, insulin is secreted in proportion to the increments in plasma glucose levels on the entry of nutrients into the circulation following food digestion and absorption. The route of administration of glucose and other nutrients markedly influences insulin secretion. When glucose is administered via the gastrointestinal tract, a much greater stimulation of insulin secretion is observed compared with similar plasma glucose levels obtained with intravenous glucose infusion.
This difference in insulin secretion between intravenous and oral glucose administration is referred to as the incretin effect and it is mediated by the release of gastrointestinal hormones. The major incretin hormones in humans are glucagon- like peptide 1 (GLP- 1) and glucose- dependent insulinotropic peptide (GIP) and these contribute to the maintenance of glucose homeostasis after meals. Other gut hormones, such as cholecystokinin (CCK), contribute to the incretin effect, although the importance of these peptides is negligible under physiological conditions.
Insulin secretion is also stimulated by protein and fat ingestion. Amino acids trigger insulin release and amplify insulin secretory pathways by acting as a substrate for the tricarboxylic acid cycle and/or redox shuttles with subsequent generation of ATP, and through direct depolarization of the plasma membrane (Figure 1). The latter is the consequence of the transmembrane transport of positively charged amino acids via specific amino acid transporters and Na+ cotransport. Lipids and free fatty acids play a crucial role in β- cell function and insulin release. In the presence of nutrients, free fatty acids modulate insulin secretion through three distinct pathways:
• Tricarboxylic acid cycle/malonyl- coenzyme A (CoA) metabolic signalling.
• Glycerolipid/free fatty acid cycling.
• Direct activation of G- protein–coupled receptors (GPCRs).
Finally, many other factors, including neuropeptides and neuronal control, contribute to the modulation of insulin secretion through a sophisticated integrated process. Stimulation of the parasympathetic nervous system increases insulin secretion while sympathetic stimulation exerts an inhibitory effect.
The pancreatic islets of Langerhans are more than just the home of the insulin- producing β cells. They contain several additional endocrine cell types, most notably glucagon- producing α cells and somatostatin- producing δ cells, which coordinate their activity in response to changes in glucose and other nutrients and modulate β- cell activity through a paracrine crosstalk between the three major endocrine cell types of the islet. At the systemic level glucagon functionally opposes the glucose- lowering effects of insulin, yet it stimulates insulin secretion through the glucagon receptor (GCGR), a class B GPCR related to the incretin receptors. Glucagon essentially acts in an incretin- like fashion amplifying glucose- stimulated insulin secretion. The glucagon paracrine effect is necessary for full insulin secretion in response to glucose stimulation. Pancreatic δ cells provide feedback control of neighbouring α and β cells through local circulation and the interstitial compartment. These interactions are essential for precise control and coordination of insulin and glucagon secretion. In addition to their paracrine activation by urocortin 3, δ cells receive selective inputs from multiple hormones, neuro transmitters, and nutrients, and integrate these into appropriate feedback modulation of insulin and glucagon secretion. Though the contributions of α and δ cells to glucose- stimulated insulin secretion are often hard to evaluate in humans, the breakdown of these paracrine connections contributes to dysregulation of insulin- and glucagon- secretory responses in diabetes.
Insulin secretion is mainly modulated in rapid feedback with plasma glucose levels, but a long- term adaptation can also occur through changes in the number of β cells, as indicated by the progressive increase in β- cell mass occurring from birth to adult hood. Expansion of β- cell mass tends to become negligible after the age of 20–30 years, yet an increase may occur under conditions of increased insulin demand such as obesity and pregnancy.
More details on the regulation of insulin secretion are available in Chapter 7, but from this brief discussion of the physiological regulation of insulin secretion, it should become apparent how abnormal insulin secretion in type 2 diabetes may arise from defective β- cell function, reduced β- cell mass, or a combination of the two.
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