Abstract (complete):
Recent studies suggest that insulin-dependent diabetes mellitus patients switched from animal to human insulin may have decreased awareness of hypoglycemia warning symptoms. The risk of severe or fatal hypoglycemia associated with the treatment of diabetes increases with age. We conducted these studies to determine if awareness of hypoglycemic warning symptoms was greater with animal than with human insulin in elderly patients with diabetes. Non-obese elderly patients with non-insulin dependent diabetes (NIDDM) (n=13, age 74 +/- 1 years, body mass index, 26.6 +/- .7 kg/m2) underwent paired hyperinsulinemic glucose clamp studies in random order. In one study, regular human insulin was infused, and in the other study, regular beef/pork insulin was infused. In all studies, plasma glucose was decreased from fasting levels to 5 mmol/L during the first 60 minutes and was then allowed to fall to 4.4, 3.8, 3.3 and 2.8 mmol/L in each subsequent hour. Subjects were unaware as to which study they were undergoing. In each study, a hypoglycemic checklist was administered, and counterregulatory hormones were measured every 15 min. Neuropsychological tests were administered, and counterregulatory hormone responses to the two insulin preparations were similar. Autonomic ( P < 0.05) and neuroglycopenic (P < 0.01) symptom scores were significantly higher during the beef/pork insulin studies.

We conclude that beef/pork insulin results in *greater* awareness of hypoglycemic warning symptoms than does human insulin with elderly patients with NIDDM. (Diabetes 44:272-277, 1995)

 [skipping research design, as well as results, for now]

Discussion:
We conducted these studies to determine if there was any potential advantage of animal over human insulin for elderly patients with diabetes. We found that, although counterregulatory hormone responses to hypoglycemia induced by the two insulins were similar, animal insulin resulted in greater awareness of hypoglycemic warning symptoms and a higher glucose threshold for awareness of symptoms.

[snip]

...If animal insulin results in greater awareness of hypoglycemic warning symptoms, what is the mechanism for the effect? In particular, why were there similar catecholamine and heart rate responses to hypoglycemia with the two insulin preparations, but reduced autonomic symptom responses with human insulin? We do not have a definitive explanation for the separation between *hormone* and *symptom* responses, although this is certainly consistent with data from other investigators [22,32].

It is likely that animal insulins cross the blood-brain barrier more readily than human insulins since they are more lipophilic [39]. It has been shown in animals that insulin stimulates glucose uptake in hypothalamus [40] and that direct stimulation of hypothalamic insulin receptors evokes behaviors consistent with hypoglycemia [41]. If hormonal responses are mediated primarily by the glucose levels in the central nervous system, while the symptom responses are mediated, at least in part, by the direct effect of insulin on neurons, this could be an explanation for the differential effect of the two insulins.

[End of material from report.

There is a lot of research being done on this, judging from the length of the list of references at the end of this article. The last paragraph quoted above, in its conclusion, shows the high likelihood of a definitive explanation eventually being found which unquestionably substantiates this inferior aspect of human insulin.

The reason that human insulin doesn't have this problem in NON-diabetics is that their pancreases are continuously infusing insulin directly into the bloodstream in microunit quantities. Since the half life of insulin (once in the blood stream) is only 3-5 minutes, the properly functioning pancreas can respond to and halt the fall of blood glucose within a minute by cutting off (if only temporarily) the secretion of insulin. But this is not possible with insulin taken by injection or infusion (which is nothing more than continuous subcutaneous injection), because such insulin continuously enters the blood stream from the point of application, and there is no way of stopping it.

(For MDI diabetics and even pump users to think that their regimens are mimicking the insulin delivery of a normal pancreas is nothing than more than wishful thinking.)

Looking at all this objectively and dispassionately, the outcome of the research that is now being carried out to investigate the "anecdotal" observations of a great number of diabetics reporting hypoglycemia unawareness, will probably show good reason why human insulin is NOT suitable for *anyone*, either by injection or infusion, the reason being that no one who uses it is free from the danger of its causing all but undetected severe hypoglycemia at some time or another, very possibly leading to unconsciousness and coma, which can also be dangerous to others as well.

Since it appears that researchers are well on their way to demonstrating in a definitive manner the physiological reason for human insulin causing this phenomenon, no longer should the answer to the question "Why does human insulin produce hypoglycemia unawareness?" be that "No one knows".

Instead, it should now be:
"Biomedical research has established the very real possibility that human insulin's marked increase of hypoglycemia unawareness is caused by the neurons in the brain which give rise to the symptoms of hypoglycemia being less activated by human insulin, due to the happenstance chemical difference of human insulin being less lipophilic (more hydrophilic) than either beef or pork".

A short article discussing the progress of this research should be written, complete with references (if no one else has done this, which is called a "review"). As Dr. Teuscher pointed out over three years ago in the Bellagio Report, so much evidence has been accumulated as to the phenomenological aspect of hypoglycemia unawareness (the fact that it has been observed a huge number of times), and so much progress on the neurophysiological explanation as to its cause has been made, that there no longer exists any possibility that the subject of the greatly increased incidence of hypoglycemia unawareness among users of human insulin will ever be discredited.