Second year undergraduate essay written for the Cell Pathology module of the Biomedical Sciences course at the University of Oxford.
//Essay title: How is insulin secreted by beta cells regulated? How can this function be affected in disease?//
Very helpful for tutorial preparation and exam ...
How is insulin secreted by beta cells regulated? How can this functi on be aff ected in
disease?
The most important function of the endocrine pancreas is the secretion of insulin that
defends us against hyperglycaemia by lowering plasma glucose level, defective insulin
secretion therefore results in diabetes mellitus. In this essay, we discuss the regulation of
insulin release in healthy individuals, followed by an account of its dysregulation in various
forms of diabetes.
To begin with, insulin is produced and secreted by pancreatic β cells which take up half the
cell mass of the islets of Langerhans, it lowers plasma glucose by acting on various target
organs such as muscles, liver and adipose tissue to regulate mobilisation and storage of
fuels. Insulin is synthesised as preproinsulin and processed into mature insulin and C-
peptide via multiple proteolytic cleavages, active insulin is then stored in secretory granules
that are released by exocytosis when stimulated by glucose, but its secretion is also under
modulation by many other hormonal and neuronal factors. With insulin as the key hormone,
the pancreas works to maintain a stable plasma glucose (fasting plasma glucose (fpg)
~5mM) which is essential as defective insulin secretion is seen in many clinical
manifestations as discussed later. As we see below, many of our current understanding
about the regulation of insulin secretion involve studying rodent models. Despite sharing
numerous similarities, there are notable differences in the architecture, innervation,
membrane channels etc. between human and rodent islet cells, so it is important to be
cautious when extrapolating data from rodents to humans.
Insulin secretion is mainly regulated by glucose, which acts to stimulate insulin release
following food ingestion to prevent hyperglycaemia. Glucose-stimulated insulin secretion
(GSIS) following a high dose of glucose is normally biphasic, with an initial rapid transient
peak followed by reduced but sustained release. In contrast, insulin response in diabetic
patients is smaller in general due to impaired β cell function. β cells couple variations in
plasma glucose concentration to regulation of exocytotic insulin release through its
electrical excitability, as illustrated in the diagram:
Firstly, plasma glucose is taken up by β cells at a plasma concentration-dependent rate.
Although it is well-established that SLC2A2-coded GLUT2 is the major glucose transporter in
rodent β cells, increasing evidence suggest predominant roles of GLUT1 and GLUT3 in
human β cells, coded for by SLC2A1 and SLC2A3 respectively. To illustrate, McCulloch et al.
, (2011) observed that mRNA expression of SLC2A1 and SLC2A3 were higher than that of
SLC2A2 in isolated human β cells, confirming similar findings by De Vos et al. (1995) that had
been largely overlooked. The role of GLUT1 and 3 in human β cells remained controversial
due to contradicting evidence reporting that SLCA2 variants elevate fpg, but some argue
that this may originate from dysregulated hepatic/renal glucose metabolism as seen in
Fanconi-Bickel syndrome, a disorder of carbohydrate metabolism caused by SLCA2
mutations. Also, GLUT1 and 3 have lower K m than GLUT2 which makes them more
compatible with the dose-response curve for human GSIS, supporting their role in human β
cells and accounting for the lower fpg in humans than rodents.
Secondly, ATP produced from glucose metabolism induces β cell electrical activity by closing
ATP-sensitive potassium (KATP) channels. Through glucose phosphorylation by glucokinase
(GCK) and mitochondrial oxidation, metabolic generation of ATP and the concomitant fall in
MgADP (i.e. increased [ATP]i:[ADP]i ratio) closes KATP channels that depolarises the cell. This
depolarisation can also be induced by uptake of other nutrient secretagogues such as the
charged amino acid arginine. Acknowledgement that GSIS relies on glucose metabolism is
based on GSIS inhibition by mitochondrial poisons like azide in rodent β cells, multiple
studies in the 1990s also showed that GSIS was absent in mitochondrial DNA-depleted β
cells (rho0 cells) of both rodents and humans, mitochondrial dysfunction was proved to be
the culprit since insulin release was restored by adding Ca 2+-raising agents or replenishing
the rho0 cells with normal mitochondria.
Thirdly, [Ca2+]i is elevated by Ca2+ influx through activating voltage-gated Ca 2+ channels as
well as calcium-induced calcium release, triggering exocytosis of insulin secretory granules.
Finally, repolarisation and successive depolarisation of β cells lead to oscillating [Ca 2+]i and
sustained insulin release that depend on the rate of glucose uptake that in turn reflects
plasma glucose concentration. In addition, glucose has an amplifying effect on insulin
release as its metabolism promotes assembly of the SNARE complex that regulates
exocytosis of insulin secretory granules.
In addition to GSIS, insulin secretion is modified by many neural and hormonal factors.
Starting with neural factors, pancreatic islets are richly innervated by both the sympathetic
(SNS) and parasympathetic nervous system (PNS). The PNS stimulates insulin release
through vagal release of acetylcholine (Ach) that activates G q-coupled muscarinic Ach
receptor, amplifying exocytosis via downstream PKC activation and IP 3-induced Ca2+ release.
On the other hand,α - and β -adrenergic SNS signalling inhibits and augments insulin
secretion respectively through modifying the cAMP-PKA signalling pathway. Neuronal
control of insulin release by the autonomic nervous system is particularly important in times
of altered metabolic state such as in exercise, when there is net α -adrenergic inhibition of
insulin secretion by the SNS neurotransmitter noradrenaline to prevent hypoglycaemia.
Besides, anticipatory insulin release before food ingestion in the cephalic phase prevents
abrupt rise in plasma glucose concentration during feeding.
Going onto hormonal control, insulin secretion is modified by endocrine as well as local
paracrine and autocrine signalling. In glucose tolerance tests, oral glucose challenge elicits a
greater insulin response than an intravenous challenge of same dosage, this difference can
be attributed to the nutrient-stimulated endocrine release of incretin hormones from the
gut. Glucagon-like peptide 1 (GLP1) is the principal incretin that potentiates GSIS via
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