Hi Allie, Thanks for stopping by. Since you are interested in research (as am I),
The Veterinary Clinics of North America: Small Animal Practice published a volume titled "Diabetes Mellitus in Cats and Dogs," edited by Chen Gilor and Thomas K. Graves, May 2023 • Volume 53 • Number 3. It's a
fascinating volume, but I had to purchase it, and I don't think it's searchable in a database, though I could be wrong about that. I'm unable to copy the entire article (though the e-book I purchased says I can copy one article without copyright violation), but here is an excerpt from a chapter entitled, "Glucose Counterregulation: Clinical Consequences of Impaired Sympathetic Responses in Diabetic Dogs and Cats." In this particular excerpt they discuss what happens when a cat/dog experiences Insulin Induced Hypoglycemia (IHH). The point I want to make in sharing this is that these doctors argue that 1) there is danger even in asymptomatic hypoglycemic episodes (not all animals exhibit symptoms even when their bg is dangerously low); and 2) experiencing hypoglycemia can be deleterious as those episodes can lead the body to experience further hypoglycemic episodes, which may not be detectable symptomatically because the body has developed a condition they call hypoglycemia unawareness.
[Here, they are discussing the progression of the body's response to IHH] Glucagon responses to hypoglycemia are largely mediated by activation of the autonomic nervous system In health, physiologic and behavioral defenses are sequentially activated as BG concentrations decline (see Fig. 1). First, when BG reduces to
low normal (80–85 mg/dL), [highlighted to point out what they identify as low-normal] endogenous insulin secretion decreases, releasing pancreatic α cells from the inhibitory paracrine effect of insulin and allowing the secretion of glucagon to occur (see Fig. 1, Table 1).3,33 Glucagon secretion is the first line of defense during hypoglycemia34: It results in increased hepatic glucose production through hepatic glycogenolysis followed by hepatic gluconeogenesis and decreased hepatic glucose uptake (see Fig. 1). By the time glucose concentrations have fallen
to ∼70 mg/dL, insulin secretion is totally shut off (see Table 1).35,36 Therefore, other mechanisms must be recruited in order to further increase glucagon secretion when glucose level reduces to less than this threshold. The activation of the autonomic nervous system by the central nervous system makes an important contribution to increased glucagon secretion during moderate-to-severe IIH: parasympathetic, sympathetic, and adrenomedullary inputs to the islet are activated by IIH and all 3 of these are capable of stimulating glucagon secretion (see Fig. 1).37 In nondiabetic animals, each of the 3 autonomic inputs to the islet is capable, by itself, of mediating most of the increase of glucagon in response to IIH. By blocking all 3 of these inputs to the islet, it was demonstrated that the activation of the autonomic nervous system mediates most of the glucagon response to IIH in healthy animals,38–41 including, nondiabetic dogs.42 Parasympathetic nerves innervating the islets become activated when BG level decreases to less than ∼70 mg/dL (see Table 1). The threshold for epinephrine (EPI) release from the adrenal medulla is a BG level less than ∼60 mg/dL (see Table 1). Finally, sympathetic nerves innervating the islets are activated when BG level decreases to less than ∼40 mg/dL (see Table 1).6 The behavioral response (sympathetic neural) to hypoglycemia (50–55 mg/dL) is ingestion of food (see Table 1, see Fig. 1).3,43 These physiologic and glucose counterregulatory responses in healthy animals combat IIH and result in euglycemia. Table 1 Physiologic responses to progressive hypoglycemia in health Glycemic Thresholds (mg/dL) System Activated (A)/Inhibited (I) Response 80–85 β cells (partially I)/α cells (A) Decrease endogenous insulin secretion Stimulate glucagon secretion 70 β cells (I) Insulin secretion shut off <70 Parasympathetic (A) Stimulate glucagon secretion <60 Adrenal medulla (A) Epinephrine release Stimulate glucagon secretion 50–55 Sympathetic neural (A) Neurogenic clinical signs Ingestion of food <40 Sympathetic (A) Stimulate glucagon secretion Decreased cognition, seizures, coma 10–20 Neuronal cell death Adapted from Cryer PE. Hypoglycemia. In: Williams Textbook of Endocrinology. Elsevier; 2016:1584.
Redirecting with permission; and Martín-Timón I. Mechanisms of hypoglycemia unawareness and implications in diabetic patients. World Journal of Diabetes. 2015;6(7):914.
https://doi.org/10.4239/wjd.v6.i7.912. Impaired counterregulatory responses to hypoglycemia in diabetes mellitus
Unfortunately, counterregulatory responses to IIH are often impaired in diabetics. With exogenous insulin therapy, a decrease in insulin levels depends on the rate of absorption and clearance of insulin and not on the level of hypoglycemia.43 Therefore, the inhibitory effect of insulin on α cells does not subside in IIH. In addition, dysfunction of sympathoadrenal system contributes to a defective glucagon response to IIH. The sympathoadrenal response is attenuated through mechanisms such as antecedent hypoglycemia, diabetic autonomic neuropathy (DAN), sympathetic islet neuropathy (humans and dogs), exercise, and sleep3,43 (see Fig. 1). The activation thresholds of different branches of the autonomic system are not fixed; they shift either to higher BG levels in poorly controlled hyperglycemic patients or to lower BG levels following episodes of hypoglycemia.44,45 Mechanisms of Impaired Counterregulatory Responses In hyperglycemia Both short-term and long-term exposures to hyperglycemia impair autonomic responses. DAN results from prolonged exposure to hyperglycemia, increased oxidative stress, and suppression of peripheral autonomic activity.46 Short-term (7 days) exposure to hyperglycemia leads to the suppression of sympathetic ganglionic neurotransmission and impairments of plasma norepinephrine and glucagon responses to preganglionic nerve stimulation.47 The site of ganglionic suppression has been localized within a specific subunit of the nicotinic receptor. In hypoglycemia Hypoglycemia-associated autonomic failure (HAAF; Fig. 2) is a reversible phenomenon that is caused by earlier episodes of hypoglycemia48 that are related to either sporadic or chronic overuse of insulin.6 Although the exact mechanism(s) have yet to be elucidated,49 under experimental conditions, exposure to as few as 2 episodes of earlier hypoglycemia is sufficient to reduce indices of autonomic neural activation (ie, PP, NE, and EPI responses) of all 3 autonomic branches during a subsequent episode in humans.48 Cortisol responses to IIH are also impaired in HAAF (at least partially).50–52 The attenuated sympathetic neural response and associated neurogenic signs can result in hypoglycemia unawareness.22 Without perception of hypoglycemia, prompt behavioral defense of carbohydrate ingestion to help restore euglycemia does not occur. Antecedent hypoglycemia lowers glycemic thresholds for both sympathoadrenal defenses and recognition of neurogenic and neuroglycopenic signs.30,45 This results in an increased risk for subsequent severe hypoglycemia in humans by 6-fold in type 1 DM (T1DM)53 and 17-fold in type 2 DM (T2DM).54 Strict avoidance of hypoglycemia for 2 to 3 weeks can reverse HAAF and hypoglycemia unawareness.
As such, ADA stresses that episodes of hypoglycemia, including asymptomatic ones, are not benign and can compromise glucose counterregulatory responses and pose an increased risk of imminent severe iatrogenic hypoglycemia.
Here is the Table 1 referred to above
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Graves, Thomas K.; Gilor, Chen. Diabetes Mellitus in Cats and Dogs, An Issue of Veterinary Clinics of North America: Small Animal Practice, E-Book (The Clinics: Veterinary Medicine) (pp. 554-556). (Function). Kindle Edition.
I should also note that Dr. Gilor is a huge proponent of CGMs because he believes that animals experience hypos much more frequently than caregivers know, and he believes the CGM gives a clearer picture (for obvious reasons).
Below are copies of the introduction and the summary pages of the article which hit the "key points" the authors make.
I'm not sure if I'm providing enough information for you to understand the point they are making. It's scientific research, so, of course, it's detailed, and it's hard to find passages that encapsulate the main points in a relatively short burst. If you are interested in the chapter, I'll be glad to make screen shots of the pages for you (again, they say I can share one article, so this is not a copyright violation).
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This last week, he's had some very active cycles with significant drops from the shot, especially in the PM cycles.
), Mary!
