Chronology of Literature on Hypoglycemic Unawareness
(Originally Published by David G. Groves in 1992)
© 1992 David Groves
Updated 04/06/04 05:20:23 PM
1921
From the first use of insulin after its isolation by Banting and Best in 1921 in Canada, patients had problems with hypoglycemia (low blood sugars) in response to the injected medication.
1941
By 1941 it is noted by Lawrence (1) that the early warning symptoms; weakness, faintness, tremors, sweating, hot or cold feelings, palpitations, appear to be similar to the symptoms of a dose of adrenaline, and that additional symptoms of hunger, visual disturbance, diplopia and tinglings also give advance warning of hypoglycemia onset in the 50-70mg/dl blood sugar range. It is further noted that should such symptoms go unrecognized or unnoticed, they are followed by mental confusion exactly simulating alcoholic intoxication, muscular twitchings, convulsions, epileptiform seizures, transient hemiplegias, and complete coma.
Finally, this article notes the first reference to a condition now called “hypoglycemic unawareness” (HGU) and notes, “The same patient may at one time experience early premonitory warnings and at another be quite unaware of an impending [sic] attack. It is obvious that these are serious dangers.” Lawrence also observes, ” … considering the large number of stupid or careless patients on insulin treatment, serious attacks and sequelae are exceedingly rare.”
1962-1981
Various articles in various sources are published on synthetic and/or recombinant DNA means for the production of “human” insulin. D. Rabinowitz et al, report (2), “… adiposity diminishes insulin sensitivity.”
Riggs (3) reports Lilly’s $40mm investment to put human insulin in large-scale production by late 1982. Goes on to recite Keen (4) The insulin from bacteria was virtually indistinguishable from porcine insulin in lowering plasma glucose levels in normal human volunteers. Most important there were no adverse side actions.” Chance, et al, report similar findings.(20).
Sotos Raptis et al report, (5) “The feeling of hypoglycemia in the group that received the BSI [Biosynthetic Human Insulin] was significantly less intense then in the PPI [Purified Pork Insulin] group.” The fact that this reduction of hypoglycemic symptoms was observed in a group as small as 5 healthy volunteers and 5 diabetic volunteers is of critical importance.
Gerich (6) reports, “… BHI appears to offer no advantage over presently available PPI in terms of prevention and treatment of lipodystrophy, insulin allergy and immune insulin resistance.”
Goldstein, et al, report (7), reciting from a 1977 study, that, “Hypoglycemia is considered a serious complication of insulin therapy…,” and that, ” … frequent or severe hypoglycemia occurred almost exclusively in patients with well controlled diabetes …”
July 1982
Peter J. Watkins recites (8), “Hypoglycemia is the major hazard of insulin treatment. … All diabetics on insulin who are reasonably well controlled will experience hypoglycemia at some stage. At its mildest it is no more than a slight inconvenience, but at its severest, when unconsciousness can occur, it is both a hazard and an embarrassment. … All diabetics must be carefully taught about the causes, symptoms and treatment of hypoglycemia. Ideally, new diabetics should be made to experience hypoglycemia during their initial education.”
He goes on to list “Early Warning Symptoms as, “Shaking, trembling; Sweating; Pins and needles in the lips and tongue; Hunger; Palpitations; Headache” and then proceeds as secondary and more advanced symptoms, to list, “Neutroglycopenia: Mild: Double vision; Difficulty in concentrating; Slurring of Speech — More Advanced: Confusion; Change of behavior; Truculence; Naughtiness in Children — Unconsciousness: Restlessness with Sweating; Epileptic fits, especially in children; Hemiplegia.”
He goes on to state, “Most diabetics experience the early warning symptoms of hypoglycemia and can take sugar before more serious symptoms develop. With increasing duration of diabetes … there is a tendency for early warning symptoms not to occur, and patients develop the more serious problems. Although this lack of warning has been attributed to autonomic neuropathy, I doubt whether this is generally the case…”
October 1982
R. B. Tattersall et al report (9), “Hypoglycemia is the commonest complication of treatment with insulin, but little is known about its true incidence. For example, in 1977 the argument that improved control might lead to increased morbidity and mortality from hypoglycemia could neither be refuted nor sustained since the basic information was lacking.” They go on to discuss why information on hypoglycemia is difficult to obtain and unreliable. The results show 37.4% of hospital admissions for hypoglycemia arose with no known cause, 13.7% from changes in insulin dose and 8.9% resulted from loss of awareness.
Early 1983
C. Goldgewicht et al report (10), ” … thinner patients have more severe reactions … “
January 1985
The 1985 PDR (physician’s Desk Reference) under all Lilly Humulin preparations under warnings (see additional warnings above) states amongst other things, The first symptoms of insulin reaction usually come on suddenly and may include fatigue, nervousness or shakiness, headache, rapid heart beat, nausea, and a cold sweat. A few Patients who experienced hypoglycemia after being transferred to Humulin have reported that these early warning symptoms were less pronounced than they were with animal source insulins.
[Note that this is perfectly consistent with the findings reported by Sotos Raptis et al (5) and that it is possible that Lilly had such a warning in place from the first bottle sold commercially in the US, this however was the oldest PDR your researcher could find.]
January 1986
The American Hospital Formulary Service “Drug Information ‘86 Listings” under 68:20:08 AntiDiabetic Agents at page 1564 states, under Pork Insulins, “… Cautions: … hypoglycemic reactions have also been reported in patients who were transferred from beef to pork insulin or from mixed beef or from beef to mixed beef/pork preparations. … Symptoms of hypoglycemia are usually manifested when the administered insulin reaches its peak action and may include hunger, pallor, fatigue, mild or profuse perspiration, headache, nausea. palpitation, numbness of the mouth, tingling in the fingers, tremors, muscle weakness, blurred or double vision, hypothermia, uncontrolled yawning, irritability, mental confusion, tachychardia, shallow breathing and loss of consciousness.
Early 1986
W. Berger and B. Althaus report (11) the existence of “hypoglycemic unawareness” with human insulins.
Early 1987
Fully 6 years after Raptis et al (5) have disclosed changed, reduced and therefor possibly lost advanced warning symptoms of hypoglycemia, at least 2 and more likely 3-5 years after Lilly has disclosed the potential loss of vital early warning symptoms before severe hypoglycemia, Squibb/Novo/Nordisk says nothing about the potential reduction in symptoms on changing to their Novolin. In a crass bid to invade Lilly’s US market share for human insulin they say only, the first warning symptoms of insulin reaction usually come on suddenly. They may include a cold sweat, fatigue, nervousness or shakiness, rapid heartbeat or nausea.” PPI shows last revision date of 10/86. [N.B.: the sweat symptom is totally adrenergic and this list from the Novolin insert is a fair symptom list for animal insulin but is totally incorrect for human insulin. Ed.]
April 21, 1987
8 hours after taking 11 units of Novolin Regular, which is supposed to peak in 2 hours and be totally out of the system in 8 hours, having taken the insulin in usual fashion before lunch at about 11am, David Groves falls unconscious at the wheel of his car around 7pm. Upon admission to the ER at Jackson Memorial Hospital with multiple trauma injuries from colliding with a parked car at a speed in excess of 65mph, Groves shows negative for alcohol and is revived by IV infusion of 50% dextrose, proving unconsciousness and accident must have been caused by severe insulin shock (hypoglycemic insulin reaction).
August 1987
Teuscher & Berger report (12) that based on their clinical experience with 3 cases of patients transferred from beef/pork insulin to Novo human insulins (reported in the article and presumably to Novo-Nordisk) there occurred multiple instances of, “peculiar and serious hypoglycemic reactions,” in the three patients. These adverse reactions were reported as they occurred. 3 in 1985 (including an auto accident and a switch back to porcine insulin after which normal early warning symptoms returned), 4 in 1986, the last of which was fatal, and 1 in early 1987. The presentation recites the Lilly warnings available in the US in 1987 and decries their absence in Europe. The study proceeds to examine 315 patients: 206 on human (Novo, Lilly, Nordisk) and 109 on beef/porcine or Porcine (Novo, Nordisk) between 9/86 and 2/87. 176 patients (of the 206 on human) were transferred between 1983 and 1987 and 30 had been started on human. 36% of the patients reported a loss of adrenergic early warning symptoms. The authors conclude, “Hypoglycemia unawareness with a blood glucose of 1-3mm/1 [18-54 mg/dl] was a characteristic finding in patients treated with human insulin. … The general well-being of such patients may seem to improve because of the reduced frequency of hypoglycemic symptoms. This observation is important for car drivers. …
The only universally accepted benefits of human insulin at present are the management of the few patients with insulin allergy and the possibility of the very rare insulin resistance. These seem to be small gains in comparison with the possible loss of well-being and the life threatening hazards associated with hypoglycemia unawareness. We are therefore concerned about the apparent marketing effort of manufacturers to influence physicians and patients to switch from animal to human insulin.”
Tattersall et al report (13) in a study of whether or not adrenal activity is responsible for hypoglycemia unawareness, “Our study shows that at mild levels of hypoglycemia subjects who recognized a low blood glucose were those with significant increases in circulating adrenaline and features of sympathetic nervous system activation. In contrast, 11/15 [11 of the total 15 subjects. ed.] patients who remained unaware had smaller increases in adrenaline and no symptoms or signs. …”
In the study of Sussman and colleagues (14) only 5 of 44 diabetic patients did not have a sympathetic response during insulin-induced hypoglycemia.” [NB Sussman's 44 were all on animal insulin while Tattersall's 15 were on Novo Actrapid Human, the equivalent of their US Novolin and we see 73% unawareness in the Tattersall group but only 11% unawareness in Sussman's group. The authors fail to make this observation.] They (Sussman et al.) go on to state that, “Subnormal increases in adrenaline with loss of warning during hypoglycemia are thought to occur only in long standing diabetics with autonomic neuropathy. However, most of our patients (with durations of diabetes from 3 to 33 years) had a reduced catecholamine response, suggesting that impaired sympathetic responses during hypoglycemia may be the rule in insulin treated patients…” [NB the human insulin is not postulated as the cause here, though it is the most obvious source of the major change in medical theory on HG that this article is suggesting.] They conclude, “We believe the major cause of severe hypoglycemic episodes to which diabetic patients with impaired adrenaline responses are prone (15) may be a failure to recognize a low blood glucose in time to correct it.” [NB Hypoglycemic unawareness defined yet again. ed.]
April 1989
Frank Lesser reports (16), and a month later, David Groves reads, “Preparations of ‘Human’ Insulin may put some insulin-dependent diabetics at life-threatening risk by depriving them of the warning symptoms of hypoglycemia,…” article cites a 1988 study from Balance, the Journal of the British Diabetic Association in which 53% of 158 patients transferred from animal insulin to human insulin, felt the warning of hypoglycemia less clear.
August 1989
Frank Lesser reports (17) on reports from forensic toxicologist, Dr. Patrick Toseland that deaths from hypoglycemic reaction have risen in Britain from 2 in 1985 to 9 in 1988 to 17 in the first half of 1989 and that at least half were patients who had switched to human insulin from animal insulin. The article goes on to underscore the fact that Lilly has been warning patients of this problem since at least 1987 while Novo had not but that in late 1989, Nordisk Wellcome [Squibb-Novo-Nordisk Britain] had begun issuing similar warnings after discussion in March with Britain’s Committee on Safety of Medicines (their equivalent of our FDA).
October 1989
Bill Richards, Staff Reporter for the Wall Street Journal reports (18) on the Toseland findings and states that the FDA “already requires drug manufacturers to include warnings with insulin products that symptoms of hypoglycemia are less pronounced with human insulin than with animal based products.”
R.J. Heine, et al, report (19) a statistically significant differential in Adrenergic Symptoms (p < 0.05), Tachycardia (p < 0.05), and Noradrenaline (p < 0.05) release in 8 healthy subjects. The porcine insulin causing more symptoms, faster heart rate and more noradrenaline. Their data also suggest an increase in neuroglycopenic symptoms and adrenaline production in the porcine insulin over the human insulin but these results are not countenanced since they are (as little as) p > 0.05.
They conclude, “The physicochemical characteristics of human and porcine insulin are different. Porcine insulin is more lipophilic than human insulin and may have greater blood-brain barrier penetration. This may explain the observed difference in autonomic response.”
1990
Dr. Robert J. Moss, Pharm. D. as Associate Director, Professional Services for Novo Nordisk Pharmaceuticals Inc. issues indemnification certificates to all US Pharmacies selling Novo insulins. Indemnity covers claims or lawsuits alleging personal injury as the result of using Novo Nordisk standard insulins, subject to use and dispensation in accordance with the PPI. [Curiously issued after the split between Squibb and Novo-Nordisk and after the insertion of the FDA required warnings into the patient package insert.]
1991
A super-plenum of articles are published “proving” that human insulin is the equivalent of porcine insulins. The proofs, however, are all flawed. Several show the results we have already displayed, but discount them for their failure to achieve statistical significance (p < 0.05), most of them use hypoglycemia symptoms NOT listed in the human insulin PPI’s and some even create new symptoms or use unconsciousness itself as a symptom. Most of the “new” symptoms are symptoms that by definition the insulin-using patient would NOT be able to identify or symptoms which would tend to prevent the patient from taking appropriate corrective action.
November 1991
Eli Lilly and Company Pharmaceutical Division mails a letter to all of the Certified Diabetes Educators in the US taking the offensive against Novo Nordisk. The letter claims, inter alia, that Novo’s promotional literature for its new biosynthetic (as opposed to semi-synthetic) human insulin, violates USP approved labeling for all human insulin products.
REFERENCES
1. “INSULIN HYPOGLYCEMIA CHANGES IN NERVOUS MANIFESTATIONS” R. D. LAWRENCE, M.D. ABERD, F.R.C.P, LANCET, Nov. 15, 1941, p.602
2. “Forearm Metabolism in obesity and its response to intra-arterial insulin. Characterization of insulin resistance and evidence of adaptive hyperinsulinism” D. Rabinowitz et al, J CLIN INVEST, 41:2173-2181
3. “Bacterial Production of Human Insulin” Arthur D. Riggs, DIABETES CARE, Vol. 4, No. 1, January-February 1981, p. 62-68
4. “Human insulin produced by recombinant DNA technology: Safety and Hypoglycemic potency in healthy men” H. Keen et al, Lancet 2: 398-401; 1980
5. “Biologic Activities of Biosynthetic Human Insulin in Healthy Volunteers and Insulin-dependent Diabetic Patients Monitored by the Artificial Endocrine Pancreas” Sotos Raptis, et al, DIABETES CARE, Vol. 4, No. 2, p. 161, March-April 1981
6. “An Appraisal of the Role of Biosynthetic Human Insulin in the Future Treatment of Diabetes Mellitus” John E. Gerich, DIABETES CARE, Vol. 4, No. 2, p. 262-63, March-April 1981
7. “A Prospective Study of Hypoglycemia in Young Diabetic Patients ” David E . Goldstein, et al, DIABETES CARE, Vol. . 4 No . 6, p. 601-605, November-December 1981
8. “ABC of Diabetes — HYPOGLYCEMIA” Peter J. Watkins, BRITISH MEDICAL JOURNAL, Vol. 285 p. 278-79, July 24, 1982
9. “Insulin-induced hypoglycemia in an accident and emergency department: the tip of an iceberg?” R. B. Tattersall, BRITISH MEDICAL JOURNAL, Vol. 285, p.1180-82, Oct. 23, 1982
10. “Hypoglycemic Reactions in 172 Type 1 (Insulin-Dependent) Diabetic Patients” C. Golgewicht et al, DIABETOLOGIA, 1983; 24: 95-99 Hypoglycemic Reactions in 172 Type 1 (Insulin-Dependent) Diabetic Patients” C. Golgewicht et al, DIABETOLOGIA, 1983; 24: 95-99
11. “Aenderungen der Hypoglykemie-Fruhsymptome bei Wechsel von tierschem Insulin auf Human insulin” W. Berger & B. Althaus, SCHWEIZ AERTZEZEIT, 1986; 67: 1130-31
12. “HYPOGLYCEMIA UNAWARENESS IN DIABETICS TRANSFERRED FROM BEEF/PORCINE INSULIN TO HUMAN INSULIN” A. Teuscher and W. G. Berger, LANCET, p. 382-85, August 15,1987
13. “INFLUENCE OF SYMPATHETIC NERVOUS SYSTEM ON HYPOGLYCEMIC WARNING SYMPTOMS” R. Tattersall, et al, LANCET, p. 359-363, August 15, 1987
14. “Failure of warning in insulin induced hypoglycemic reactions” K. E. Sussman, et al, DIABETES, 1963; 12: 38-45
15. “Identification of patients of type 1 diabetic patients at increased risk for hypoglycemia during intensified therapy” N.H. White et al, N ENG J MED, 1983; 308: 485-91
16. “‘HUMAN’ INSULIN LOSES ITS CLEAN APPEAL” Frank Lesser, NEW SCIENTIST, p. 30, April 15, 1989
17. “HUMAN INSULIN COMES UNDER CLOSE SCRUTINY AS NUMBER OF DEATHS RISE” Frank Lesser, NEW SCIENTIST, p. 22 August 19, 1989
18. “REPORTS OF DEATHS AMONG U.K. DIABETICS USING HUMAN INSULIN STIR CONCERN HERE” Bill Richards, WALL STREET JOURNAL, Metro DC edition sometime in or near the week of 10/23-30/1989
19. “RESPONSES TO HUMAN AND PORCINE INSULIN IN HEALTHY SUBJECTS” R.J. Heine, et al, LANCET, p. 946-49, October 21,1989
20. “Clinical, physical and biological properties of biosynthetic human insulin” R.E. Chance, et al, DIABETES CARE, 1981; 4: 147-54
Dave Groves dggroves@earthlink.net
Note: David died a few years ago, so the above address is probably no longer valid–Michael
