Week 1 [Insulin + Glucose + ANS]

Hello internets. My name is Scotty Vincent & I am one quarter of the cooperative team ‘The Neurocontributors’. We are scientifically-inclined students enrolled in COGS 163 at UC San Diego. Over the next 10 weeks, our group will flail about wildly in an attempt to make the jargon of important scientific literature more accessible.

This weeks journals focused on the basic mechanisms underlying glucose regulation with specific attention given to two types of regulation: (1) local regulation and (2) cephalically-mediated regulation. Glucose — aka C6H12O6 — is a simple sugar and crucial energy source for living organisms. In the body (peripherally), it is either burned immediately or stored as glycogen. In the brain (centrally), ATP or adenosine triphosphate is produced as a byproduct during glycolysis, which converts glucose to pyruvate — a key player in metabolic processes within a cell. ATP is used by metabolic processes within the cell.

Glucose in the bloodstream is regulated by insulin, a 51-amino-acid protein along with other peptides that are synthesized within and secreted by endocrine cells in the pancreas. Too much glucose in the blood (hyperglycemia) or too little (hypoglycemia) are both undesirable. Glucose levels rise naturally in response to food intake (they are esp. sensitive to foods high in sugar) and, as we’ve learned this week, the pancreas and the central nervous system (CNS) work together to maintain glucose homeostasis.

Environmental, biological, and lifestyle choices all have a driving influence on blood glucose levels. Exercise, diet, medication, sleep habits, etc. all work together to modulate a basal — or “normally expected/occuring” — level of blood glucose. Over time, our daily decisions come to determine our body’s ability to regulate blood glucose (as well as other crucially-important metabolic hormones).

Artificial sweeteners like sucralose (Splenda) and aspartame (often found in diet sodas) are interpreted by the body as regular sugar — this leads to an insulin spike in the absence of glucose. The subsequently increased levels of insulin in the bloodstream act upon basal glucose levels, causing a hypoglycemic response — that’s bad. Regular intake of artificial sweeteners can lead to an insensitized or ineffective insulin response.


  • Pancreas = small, hand-sized organ that sits behind the stomach. It is part of the endocrine system and, as such, is involved in the regulation of blood hormone levels. It receives both parasympathetic and sympathetic inputs from the autonomic and central nervous systems.
  • Islets of Langerhan = clusters of endocrine cells, surrounded by exocrine cells. This tissue is a combination of β cells, α cells, δ cells, ε cells, & F cells and makes up between 1–2% of all pancreatic tissue. These islets secrete hormones into blood vessels and are richly innervated by the CNS. Each type of cell in this cluster is responsible for the creation and release of hormones that have a regulatory effect on the appetite cascade via the bloodstream.
  • Blood Brain Barrier (BBB) = a selectively-permeable system of layers that separates the capillaries (which carry blood to the brain) from the extracellular fluid (BECF) and cerebral spinal fluid (CSF). Specialized glucose transport proteins (GLUT1) in blood capillaries move glucose molecules across the BBB for metabolic use.



When blood glucose rises (i.e. after a meal with carbohydrates or fats), GLUT2 receptors on β cells in pancreatic islets sense how much glucose is present (by transporting that glucose into the cell itself), and release a certain amount of insulin in response. Most of the cells in the Islets of Langerhan are β cells. This insulin is pleiotropic — meaning it has many effects. For example:

  • β cells → release insulin that binds to insulin receptors on skeletal muscle cells, causing GLUT4 receptors to translocate to the membrane of the skeletal muscle cell. This glucose transporter protein moves glucose into the cell for storage as glycogen through a process called glycogen synthesis or for immediate use through cell metabolism.
  • β cells → release insulin that moves into liver cells, leading to (1) storage of glucose as glycogen, (2) activation of protein synthesis, and (3) activation of fatty acid synthesis.
The liver, which normally releases glucose into the blood after completion of “Glycogenolysis” (the breakdown of glycogen) and “Gluconeogenesis” (the synthesis of glucose by amino acids), is occupied during alcohol consumption and not able to convert glycogen to glucose as effectively as normal. This less-commonly known effect makes alcohol consumption dangerous ground for diabetics. You can read more about blood sugar factors here.

When blood glucose dips (i.e. when your body has begun to produce insulin in preparation for food — driven by the cephalic phase, which we will talk about later), the body calls upon glucagon, a peptide hormone released by α cells in the Islets of Langerhan, to modulate blood sugar levels by releasing stored glucose into the bloodstream.

These α cells detect low glucose levels in the bloodstream and release glucagon. Glucagon then travels to the liver where it binds with glucagon receptors. These receptors drive the activation of second messengers inside the brain (cyclic AMP or ‘cAMP’). Second messengers are part of molecular systems which change the internal states of cells in response to outside factors. Once active, cAMP activates a cascade of enzymes which ultimately take energy stores (glycogen) and convert them into glucose for release directly into the blood stream.


The body has a nuanced system for regulating blood glucose levels within the bloodstream. However, an understanding of local regulation doesn’t offer a comprehensive view of the body’s pursuit of glucose homeostasis. By nature, our systems are anticipatory; human beings are masters of priming and shortcuts.

The effects of glucose levels in the blood stream are (at least in part) a matter of timing. The function which describes the influence of glucose on the rest of our bodily functions is a combination of (1) relative concentration and (2) time — being hypoglycemic for 30 seconds is much different from being hypoglycemic for 3 hours. So, if regulation is a time-sensitive matter, would we expect glucose to only be regulated locally? reflexively? Or, given the brain’s powerful ability to anticipate and the importance of eating, would it make sense that the body has some other system which anticipates changes in glucose levels?

Have you ever gone to pick up a heavy suitcase, only to find it empty? To pick up the heavy bag, your body anticipated the weight by creating tension throughout your posterior chain and spreading your legs slightly. Because the suitcase is empty, this tension is disproportionate for the task at hand; the bag flies off of the ground unnecessarily. This anticipatory response is meant to save you time by priming your body to produce movement but it does not work perfectly. This priming is similar to the body’s cephalically-mediated insulin response; this type of failure mirrors the anticipation of food that never comes, resulting in hypoglycemia.

The autonomic nervous system is the division of the nervous system responsible for unconscious behavior (breathing, digestion, etc.). It is divided into two familiar parts: the parasympathetic nervous system (PNS) and the sympathetic nervous system (SNS). These systems work in concert, though their activity is often inversely proportionate. The PNS is commonly thought of as your “rest and digest” system — it primes the body for a state of recovery and relaxation. The SNS is our system for “fight and flight” — it readies the body for metabolizing fuel and utilizing stored energy in preparation of movement.

The hypothalamus (part of the human midbrain) accepts modulated inputs from the thalamus and various parts of the cortex. It is deeply interconnected with body’s endocrine system and innervates the pancreas by way of the mesenteric ganglia (near the spinal cord) and the vagus nerve.

The sympathetic and parasympathetic innervations onto the pancreas a swath of complicated affects — noradrenaline, acetylcholine, galvanic, PACAP each create a cascade of modulatory effects within insulin-secreting β cells. Speaking generally:

  • Parasympathetic activity → increased insulin secretion and decreased glucose in bloodstream.
  • Sympathetic activity → increased glucagon secretion (α cells) decreased insulin secretion (β cells) & increased glucose in bloodstream

This means that your body is less acutely capable of cephalically regulating blood glucose levels during exercise, though regular exercise is encouraged as a first course of treatment for near-diabetics.

Increased endurance has been shown to cause an increased concentration of GLUT4 receptors — more GLUT4 receptors on skeletal muscle cells means your body needs less insulin to regulate blood glucose levels.
complicated β cell shenanigans.

Among those factors with complicated effects on insulin secretion, noradrenaline stands out as having dualist tendencies. It acts in the following ways:

  1. Noradrenaline → activates G protein → G protein binds to adenyly cyclase (AC) → AC turns adenosine triphosphate into cAMP → cAMP binds to regulatory PKA → releases catalytic PKA → catalytic PKA travels to the nucleus and initiates CREB cycle → creation of proteins needed for insulin synthesis (preproinsulin, proinsulin, etc.) → increased insulin.
  2. Noradrenaline → activates G protein → G protein binds to metabotropic potassium ion (K+) channels → cell is hyperpolarized → calcium ion (Ca2+) is unable to enter the cell → decreased insulin.

Noradrenaline or norepinephrine is a neuromodulator (& hormone) which acts within the CNS, ANS, and endocrine systems to mobilize the body and brain for action. Knowing this, we would expect a net result of decreased insulin (see our earlier discussion re: “sympathetic activity”). This is true; but what, then, is the purpose of it’s dual action? The rest of this blog is purely scientific rambling + curiosity.

In justification of the dualistic system, I propose the following explanation:

The K+ pathway exclusively (in this case) deals with the influx of Ca2+. Elsewhere in the nervous system, calcium ion influx is the precursor to the binding of synaptic vesicles to active zones on terminal membranes. It stands to reason that Ca2+ is similarly used in this pathway to bind the localized vesicles (containing insulin) to the cell membrane for secretion.
The PKA/CREB pathway is in the business of building proteins. These proteins ultimately (in this case) become insulin. Sympathetic activation (like during exercise or emotional stress) leads to an increase in noradrenaline in the nervous system and in the bloodstream. This noradrenaline leads to the creation of insulin, but because of the absence of Ca2+ (noradrenaline’s 1st mechanism), insulin is not secreted but it is primed. This follows anecdotal knowledge of post-exercise and post-exam hunger pangs — seemingly related to the cephalic phase of the appetite cascade.
I’m certainly interested in pursuing this idea further, though it may already be substantiated in the literature without my knowledge.

Scotty out.

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