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Adverse Effects of Exogenous Insulin

Clinical Features, Management and Prevention

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  • Drug Experience
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Summary

Insulin has been in therapeutic use for around 70 years, and the range of adverse effects associated with its use is very limited. Insulin allergy and other local cutaneous reactions, which were common with the early insulins, are now rarely seen with highly purified and biosynthetic preparations. By far the most important complication of exogenous insulin is hypoglycaemia, which affects almost all insulin-treated patients and is largely a manifestation of nonphysiological insulin regimens and routes of administration. The problem of hypoglycaemia unawareness is now being increasingly recognised, with onset of severe neuroglycopenia and coma which is not preceded by the characteristic warning symptoms associated with autonomic activation. This can occur with excessively tight glycaemic control, and this situation is usually reversible. More commonly, however, hypoglycaemia unawareness is a chronic problem which is predominantly a feature of long duration of diabetes. Although individual episodes of hypoglycaemic coma can usually be effectively treated with parenteral dextrose or glucagon, management of patients with chronic hypoglycaemia unawareness is a difficult clinical challenge, with limited therapeutic options. In the past few years, there has been concern that the use of human insulin preparations may predispose to hypoglycaemia unawareness. The evidence for and against this is discussed, although at present it is difficult to draw any absolutely firm conclusions.

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References

  • Abramson EA, Arky RA, Woeber KA. Effects of propranolol on the hormonal and metabolic responses to insulin-induced hypoglycaemia. Lancet 2: 1386–1388, 1966

    PubMed  CAS  Google Scholar 

  • Adamson U, Lins P-E, Efendic S, Hamberger B, Wajngot A. Impaired counterregulation of hypoglycaemia in a group of in-sulindependent diabetics with recurrent episodes of severe hypoglycaemia. Acta Medica Scandinavica 216: 215–222, 1984

    PubMed  CAS  Google Scholar 

  • Agardh CD, Kalimo H, Olsson Y, Siesjo BR. Hypoglycaemic brain injury. Acta Neuropathologica 50: 31–41, 1980

    PubMed  CAS  Google Scholar 

  • Amiel SA, Sherwin RS, Simonson DC, Tamborlane WV. Effect of intensive insulin therapy on glycemic thresholds for counterregulatory hormone release. Diabetes 37: 901–907, 1988

    PubMed  CAS  Google Scholar 

  • Amiel SA, Tamborlane WV, Simonson DC, Sherwin RS. Defective glucose counter-regulation after strict glycemic control of insulin-dependent diabetes mellitus. New England Journal of Medicine 316: 1376–1383, 1987

    PubMed  CAS  Google Scholar 

  • Anderson JA, Adkinson NF. Allergic reactions to drugs and biologic agents. Journal of the American Medical Association 258: 2891–2899, 1987

    PubMed  CAS  Google Scholar 

  • Arky RA, Veverbrants E, Abramson EA. Irreversible hypoglycaemia. A complication of alcohol and insulin. Journal of the American Medical Association 206: 575–578, 1968

    PubMed  CAS  Google Scholar 

  • Asplin CM, Hartog M. Serum free insulin concentrations during the treatment of diabetic coma and pre-coma with low dose intramuscular insulin. Diabetologia 13: 475–480, 1977

    PubMed  CAS  Google Scholar 

  • Balodimos C, Root HF. Hypoglycaemic insulin reactions without warning symptoms. Journal of the American Medical Association 171: 261–266, 1959

    PubMed  CAS  Google Scholar 

  • Banting FG, Franks WR, Cairns S. Anti-insulin activity of serum of insulin treated patients. American Journal of Psychiatry 95: 562–565, 1938

    Google Scholar 

  • Berger M. Much ado about hypoglycaemia (un)awareness. Diabetologia 30: 829–833, 1987

    PubMed  CAS  Google Scholar 

  • Berger M, Cuppers HJ, Hegner H, Jorgens V, Berchtold P. Absorption kinetics and biologic effects of subcutaneously injected insulin preparations. Diabetes Care 5: 77–91, 1982

    PubMed  CAS  Google Scholar 

  • Berger W, Keller U, Honegger B, Jaeggi E. Warning symptoms of hypoglycaemia during treatment with human and porcine insulin in diabetes mellitus. Lancet 1: 1041–1044, 1989

    PubMed  CAS  Google Scholar 

  • Berlin I, Grimaldi A, Landault C, Zoghbi F, Thervet F, et al. Lack of hypoglycaemic symptoms and decreased beta-adrenergic sensitivity in insulin-dependent diabetic patients. Journal of Clinical Endocrinology and Metabolism 66: 273–278, 1988

    PubMed  CAS  Google Scholar 

  • Berson S, Yalow RS. Quantitative aspects of the reaction between insulin and insulin binding antibody. Journal of Clinical Investigation 38: 1996–2016, 1959

    PubMed  CAS  Google Scholar 

  • Bhatia V, Wolfsdorf JI. Severe hypoglycaemia in youth with insulin-dependent diabetes mellitus: frequency and causative factors. Pediatrics 88: 1187–1193, 1991

    PubMed  CAS  Google Scholar 

  • Binder C, Lauritzen T, Faber O, Pramming S. Insulin pharmacokinetics. Diabetes Care 7: 188–199, 1984

    PubMed  Google Scholar 

  • Binder Nielsen A, Jorgensen K. The absorption of an acid and a neutral solution after subcutaneous injection into different regions in diabetic patients. Scandinavian Journal of Clinical and Laboratory Investigation 19: 156–163, 1967

    Google Scholar 

  • Blackman JD, Towle VL, Lewis GF, Spire J-P, Polonsky KS. Hypoglycaemic thresholds for cognitive dysfunction in humans. Diabetes 39: 828–835, 1990

    PubMed  CAS  Google Scholar 

  • Bock T, Pedersen CR, Josefsen K, Bottazzo GF, Palmer JP, et al. No risk of diabetes after insulin-shock treatment. Lancet 339: 1504–1506, 1992

    PubMed  CAS  Google Scholar 

  • Boden G, Soriano M, Hoeldke RD, Owen OE. Counterregulatory hormone release and glucose recovery after hypoglycemia in non insulin-dependent diabetic patients. Diabetes 32: 1055–1059, 1983

    PubMed  CAS  Google Scholar 

  • Bolli GB, De Feo P, Compagnucci P, Catechini MG, Angeletti G, et al. Abnormal glucose counterregulation in insulin-dependent diabetes mellitus: interaction of anti-insulin antibodies and impaired glucagon and epinephrine secretion. Diabetes 32: 134–141, 1983

    PubMed  CAS  Google Scholar 

  • Olli GB, Dimitriadis GD, Pehling GB, Baker BA, Haymond MW, et al. Abnormal glucose counterregulation after subcutaneous insulin in insulin-dependent diabetes mellitus. New England Journal of Medicine 310: 1706–1711, 1984a

    Google Scholar 

  • Bolli GB, Gottesman IS, Campbell PJ, Haymond MW, Cryer PE, et al. Glucose counter-regulation and waning of insulin in the Somogyi phenomenon (post hypoglycaemic hyperglycaemia). New England Journal of Medicine 311: 1214–1219, 1984b

    PubMed  CAS  Google Scholar 

  • Bolli GB, Tsalikian E, Haymond MW, Cryer PE, Gerich JE. Defective glucose counterregulation after subcutaneous insulin in noninsulin-dependent diabetes mellitus. Journal of Clinical Investigation 73: 1532–1541, 1984c

    PubMed  CAS  Google Scholar 

  • Casparie AF, Elving LD. Severe hypoglycaemia in diabetic patients: frequency, causes, prevention. Diabetes Care 8: 141–145, 1985

    PubMed  CAS  Google Scholar 

  • Clausen Sjobom N, Lins P-E, Adamson U, Theodorsson E. A comparative study on the hormonal responses to insulin-induced hypoglycaemia using semi-synthetic human insulin and pork insulin in patients with Type 1 diabetes mellitus. Diabetic Medicine 7: 775–779, 1990

    Google Scholar 

  • Colagiuri S, Miller JJ, Petocz P. Double-blind crossover comparison of human and porcine insulins in patients reporting lack of hypoglycaemia awareness. Lancet 339: 1432–1435, 1992

    PubMed  CAS  Google Scholar 

  • Collier A, Steedman DJ, Patrick AW, Nimmo GR, Matthews DM, et al. Comparison of intravenous glucagon and dextrose in treatment of severe hypoglycemia in an accident and emergency department. Diabetes Care 10: 712–751, 1987

    PubMed  CAS  Google Scholar 

  • Corp E, Woods SC, Porte D, Dorsa D, Figlewicz D, et al. Localisation of insulin binding sites in the rat hypothalamus by quantitative autoradiography. Neuroscience Letters 79: 17–22, 1986

    Google Scholar 

  • Corrali RJM, Frier BM, Davidson NMcD, Hopkins WM, French EB. Cholinergic manifestations of the acute autonomic reaction to hypoglycaemia in man. Clinical Science 64: 49–53, 1983

    Google Scholar 

  • Corrali RJM, Frier BM, McClemont E, Taylor S, Christie N. Re-covery mechanisms from acute hypoglycemia in complete tetraplegia. Paraplegia 17: 314–318, 1979

    Google Scholar 

  • Cryer PE. Glucose counterregulation in man. Diabetes 30: 261–264, 1981

    PubMed  CAS  Google Scholar 

  • Cryer PE. Iatrogenic hypoglycaemia as a cause of hypoglycemia-associated autonomic failure in IDDM: a vicious cycle. Diabetes 41: 255–260, 1992

    PubMed  CAS  Google Scholar 

  • Cryer PE, White NH, Santiago JV. The relevance of glucose counterregulatory systems to patients with insulin-dependent diabetes mellitus. Endocrine Reviews 7: 131–139, 1986

    PubMed  CAS  Google Scholar 

  • Daneman D, Frank M, Perlman K, Tamm J, Ehrlich R. Severe hypoglycaemia in children with insulin-dependent diabetes mellitus: frequency and predisposing factors. Journal of Pediatrics 115: 681–685, 1989

    PubMed  CAS  Google Scholar 

  • DCCT Research Group. Diabetes Control and Complications Trial (DCCT): results of feasibility study. Diabetes Care 10: 1–19, 1987

    Google Scholar 

  • DCCT Research Group. Epidemiology of severe hypoglycemia in the Diabetes Control and Complications Trial. American Journal of Medicine 90: 450–459, 1991

    Google Scholar 

  • Diamond M, Hallarman L, Starich-Zych K, Jones TW, Connolly-Howard M, et al. Suppression of counterregulatory response to hypoglycaemia by insulin per se. Journal of Clinical Endocrinology and Metabolism 72: 1388–1390, 1991

    PubMed  CAS  Google Scholar 

  • Dillon RS. Improved serum insulin profiles in diabetic individuals who massaged their insulin injection sites. Diabetes Care 6: 399–401, 1983

    PubMed  CAS  Google Scholar 

  • Dixon K. Measurement of antibodies to insulin in serum. Clinical Chemistry 20: 1275–1281, 1974

    PubMed  CAS  Google Scholar 

  • Egger M, Davey-Smith G, Imhoof H, Teuscher A. Risk of severe hypoglycaemia in insulin treated diabetic patients transferred to human insulin: a case controlled study. British Medical Journal 303: 617–621, 1991b

    PubMed  CAS  Google Scholar 

  • Egger M, Davey-Smith G, Teuscher AU, Teuscher A. Influence of human insulin on symptoms and awareness of hypoglycaemia: a randomised double blind crossover trial. British Medical Journal 303: 622–626, 1991c

    PubMed  CAS  Google Scholar 

  • Egger M, Gschwand S, Davey Smith G, Zuppinger K. Increasing incidence of hypoglycemic coma in children with IDDM. Diabetes Care 14: 1001–1005, 1991a

    PubMed  CAS  Google Scholar 

  • Elrick H, Witten TA, Arai Y. Glucagon treatment of insulin reactions. New England Journal of Medicine 258: 476–480, 1958

    PubMed  CAS  Google Scholar 

  • Ferrer JP, Esmatjes E, Gonzalez-Clemente JM, Goday A, Conget I, et al. Symptomatic and hormonal hypoglycaemic responses to human and porcine insulin in patients with Type 1 diabetes mellitus. Diabetic Medicine 9: 522–527, 1992

    PubMed  CAS  Google Scholar 

  • Fisher BM, Gray CE, Beastall GH, Frier BM. Responses to acute insulin-induced hypoglycaemia in diabetic patients: a comparison of short-acting porcine and human insulins. Diabetes Research 8: 1–8, 1988

    PubMed  CAS  Google Scholar 

  • Frid A, Linde Where do lean diabetics inject their insulin? A study using computed tomography. British Medical Journal 292: 1638, 1986

    PubMed  CAS  Google Scholar 

  • Frier BM. Hypoglycaemia and diabetes. Diabetic Medicine 3: 513–525, 1986

    PubMed  CAS  Google Scholar 

  • Galloway JA, Spradlin CT, Root MA, Fineberg SE. The plasma glucose response to neutral regular and NPH biosynthetic human and purified porcine insulins. Diabetes Care 4: 183–188, 1981

    PubMed  CAS  Google Scholar 

  • Gerich JE, Langlois M, Noacco C, Karam JH, Forsham PH. Lack of glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic alpha cell defect. Science 182: 171–173, 1973

    PubMed  CAS  Google Scholar 

  • Gill GV, Jones KE. Beef to human insulin: dose for dose? Lancet 1: 1305, 1988

    Google Scholar 

  • Ginsberg J, Paton A. Effects of insulin after adrenalectomy. Lancet 2: 491–494, 1956

    Google Scholar 

  • Goldgewicht Slama D, Papoz L, Tchobroutsky D. Hypoglycaemic reactions in 172 Type 1 (insulin-dependent) diabetic patients. Diabetologia 24: 95–99, 1983

    Google Scholar 

  • Haist RE, Campbell J, Best CH. The prevention of diabetes. New England Journal of Medicine 223: 607–615, 1940

    Google Scholar 

  • Heine RJ, van der Heyden EAP, van der Veen EA. Responses to human and porcine insulin in healthy subjects. Lancet 2: 946–949, 1989

    PubMed  CAS  Google Scholar 

  • Heller SR, Cryer PE. Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after 1 episode of hypoglycemia in nondiabetic humans. Diabetes 40: 223–226, 1991

    PubMed  CAS  Google Scholar 

  • Heller SR, Macdonald IA, Tattersall RB. Counterregulation in Type 2 (non-insulin-dependent) diabetes mellitus: normal endocrine and glycaemic responses, up to 10 years after diagnosis. Diabetologia 30: 924–929, 1987

    PubMed  CAS  Google Scholar 

  • Hepburn DA, Deary IJ, Frier BM. Classification of symptoms of hypoglycaemia in insulin-treated diabetic patients using factor analysis: relationship to hypoglycaemia unawareness. Diabetic Medicine 9: 70–75, 1992

    PubMed  CAS  Google Scholar 

  • Hepburn DA, Deary IJ, Frier BM, Patrick AW, Quinn JD, et al. Symptoms of acute insulin induced hypoglycemia in humans with and without IDDM: factor-analysis approach. Diabetes Care 14: 949–957, 1991a

    PubMed  CAS  Google Scholar 

  • Hepburn DA, Eadington DW, Patrick AW, Colledge NR, Frier BM. Symptomatic awareness of hypoglycaemia: does it change on transfer from animal to human insulin? Diabetic Medicine 6: 586–590, 1989b

    PubMed  CAS  Google Scholar 

  • Hepburn DA, Patrick AW, Brash HM, Thomson I, Frier BM. Hypoglycaemia unawareness in Type 1 diabetes: a lower plasma glucose is required to stimulate sympatho-adrenal activation. Diabetic Medicine 8: 934–945, 1991b

    PubMed  CAS  Google Scholar 

  • Hepburn DA, Patrick AW, Eadington DW, Ewing DJ, Frier BM. Unawareness of hypoglycaemia in insulin-treated diabetic patients: prevalence and relationship to autonomie neuropathy. Diabetic Medicine 7: 711–717, 1990

    PubMed  CAS  Google Scholar 

  • Hepburn DA, Steel JM, Frier BM. Hypoglycaemic convulsions cause serious musculoskeletal injuries in patients with IDDM. Diabetes Care 12: 32–34, 1989a

    PubMed  CAS  Google Scholar 

  • Hilsted J, Madsbad S, Krarup T, Sestoft L, Christensen NJ, et al. Hormonal, metabolic and cardiovascular responses to hypog-lycemia in diabetic autonomic neuropathy. Diabetes 30: 626–633, 1981

    PubMed  CAS  Google Scholar 

  • Hoeldtke RD, Boden G, Shuman CR, Owen OE. Reduced epinephrine secretion and hypoglycemia unawareness in diabetic autonomie neuropathy. Annals of Internal Medicine 96: 459–462, 1982

    PubMed  CAS  Google Scholar 

  • Home PD, Alberti KGMM. Human insulin. Clinical Endocrinology and Metabolism 11: 453–483, 1982

    CAS  Google Scholar 

  • Jones TW, Caprio S, Diamond MP, Hallarman L, Boulware SD, et al. Does insulin species modify counterregulatory hormone response to hypoglycemia? Diabetes Care 14: 728–731, 1991

    PubMed  CAS  Google Scholar 

  • Joslin E, Gray H, Root H. Insulin in hospital, home. Journal of Metabolic Research 21: 655–699, 1924

    Google Scholar 

  • Kalimo H, Olsson Y. Effects of severe hypoglycaemia on the human brain: neuropathological case reports. Acta Neurologica Scandinavica 62: 345–356, 1980

    PubMed  CAS  Google Scholar 

  • Kern W, Lieb Kerner W, Born J, Fehm HL. Differential effects of human and pork insulin-induced hypoglycemia in neuronal function in humans. Diabetes 39: 1091–1098, 1990

    PubMed  CAS  Google Scholar 

  • Kerr D, Macdonald IA, Tattersall RB. Adaptation to mild hypo-glycaemia in normal subjects despite sustained increases in counter-regulatory hormones. Diabetologia 32: 249–254, 1989

    PubMed  CAS  Google Scholar 

  • Kerr D, Reza M, Smith N, Leatherdale BA. Importance of insulin in subjective, cognitive and and hormonal responses to hypoglycemia in patients with IDDM. Diabetes 39: 1057–1062, 1991

    Google Scholar 

  • Kloppel G. ’Insulin’ induced insulitis. Acta Endocrinologica 83 (Suppl.): 107–121, 1976

    Google Scholar 

  • Knight G, Boulton AJM, Drury J, Gamsu DS, Moses JL, et al. A feasability study of the use of continuous subcutaneous insulin infusion in a diabetic clinic: patients choice of treatment. Diabetic Medicine 1: 267–272, 1984

    PubMed  CAS  Google Scholar 

  • Knight G, Jennings AM, Boulton AJM, Tomlinson S, Ward JD. Severe hypoglycaemia and ketoacidosis during routine treatment with an insulin pump. British Medical Journal 291: 371–372, 1985

    PubMed  CAS  Google Scholar 

  • Koivisto VA, Felig P. Effects of leg exercise on insulin absorption in diabetic patients. New England Journal of Medicine 298: 79–83, 1978

    PubMed  CAS  Google Scholar 

  • Koivisto VA, Fortney S, Hendler R, Felig P. A rise in ambient temperature augments insulin absorption in diabetic patients. Metabolism 30: 402–405, 1981

    PubMed  CAS  Google Scholar 

  • Kurtz AB, Matthews JA, Nabarro JDN. Insulin binding antibody: reaction differences with bovine and porcine insulins. Diabetologia 15: 19–22, 1978

    PubMed  CAS  Google Scholar 

  • Lager I, Attvall S, Blohme G, Smith U. Altered recognition of hypoglycaemic symptoms in Type 1 diabetes during intensified control with continuous subcutaneous insulin infusion. Diabetic Medicine 3: 322–325, 1986

    PubMed  CAS  Google Scholar 

  • Langan SJ, Deary IJ, Hepburn DA, Frier BM. Cumulative cognitive impairment following recurrent severe hypoglycaemia in adult patients with insulin-treated diabetes mellitus. Diabetologia 34: 37–344, 1991

    Google Scholar 

  • Lawrence RD. Insulin hypoglycaemia: changes in nervous manifestations. Lancet 2: 602, 1941

    Google Scholar 

  • Lawrence RD, Meyer A, Nevin S. The pathological changes in the brain in fatal hypoglycaemia. Quarterly Journal of Medicine 11: 181–201, 1942

    CAS  Google Scholar 

  • Le Compte PM, Steinke J, Soeldner JS, Renold AE. Changes in the islets of Langerhans in cows injected with heterologous and homologous insulin. Diabetes 15: 586–596, 1966

    Google Scholar 

  • Linde B. Dissociation of insulin absorption and blood flow during massage of a subcutaneous injection site. Diabetes Care 9: 570–574, 1986

    PubMed  CAS  Google Scholar 

  • Maddock S, Trimble H. Prolonged insulin hypoglycemia without symptoms. Journal of the American Medical Association 91: 616–621, 1928

    CAS  Google Scholar 

  • Mann NP, Johnston DI, Reeves WG, Murphy MA. Human insulin and porcine insulin in the treatment of diabetic children: comparison of metabolic control and insulin antibody production. British Medical Journal 287: 1580–1582, 1983

    PubMed  CAS  Google Scholar 

  • Maran A, Macdonald IA, Gale EAM, Amiel SA. Human insulin does not affect the presentation of hypoglycaemia in Type 1 diabetes: a clinical and laboratory study. Abstract no. A40. Diabetic Medicine 9(Suppl. 1): 11 A, 1992

    Google Scholar 

  • Mathias CJ, Frankel HL, Turner RC, Christensen NJ. Physiologic responses to insulin hypoglycemia in spinal man. Paraplegia 17: 319–326, 1979

    PubMed  CAS  Google Scholar 

  • Matthew G, Fleming MD, Stewart IS. Cutaneous insulin reaction resembling acanthosis nigricans. Archives of Dermatology 122: 1054–1056, 1986

    Google Scholar 

  • Matthews DM, Patrick AW, Collier A, Kellett HA, Macintyre CCA, et al. Awareness and use of glucagon amongst insulin treated diabetics. British Medical Journal 293: 367–368, 1986

    PubMed  CAS  Google Scholar 

  • Mecklenburg RS, Benson EA, Benson JW, Fredlund PN, Guinn T, et al. Acute complicates associated with insulin infusion pump therapy: reports of experience with 161 patients. Journal of the American Medical Association 252: 3265–3269, 1984

    PubMed  CAS  Google Scholar 

  • Mikratou A, Ryan C, Veneman T, Mokan M, Jenssen T, et al. Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. American Journal of Physiology 260: E67–E74, 1990

    Google Scholar 

  • Mühlhauser I, Berger M, Sonnenberg D, Koch J, Jorgens V, et al. Incidence and management of severe hypoglycemia in 434 adults with insulin-dependent diabetes mellitus. Diabetes Care 8: 274–278, 1985a

    Google Scholar 

  • Mühlhauser I, Koch J, Berger M. Pharmacokinetics and bioavailability of injected glucagon: differences between intra-muscular, subcutaneous and intravenous administration. Diabetes Care 8: 39–42, 1985b

    PubMed  Google Scholar 

  • Murray DP, Keenan P, Gayre E, Salmon P, Tompkin GH, et al. A randomized trial of the efficacy and acceptability of a pen injector. Diabetic Medicine 5: 570–574, 1988

    Google Scholar 

  • Owens DR, Jones IR, Birtwell AJ, Burge CTR, Luzio S, et al. Study of porcine and human isophane insulin in normal subjects. Diabetologia 26: 261–265, 1984

    PubMed  CAS  Google Scholar 

  • Owens DR, Vora JP, Tronier B, Keller U, Luzio S, et al. Hormonal counterregulatory responses to human (semisynthetic and recombinant DNA) and porcine insulin induced hypoglycaemia. Diabetes Research 8: 17–20, 1988

    PubMed  CAS  Google Scholar 

  • Patrick AW, Bodmer CW, Tieszen KL, White MC, Williams G. Human insulin and awareness of acute hypoglycaemic symptoms in insulindependent diabetes. Lancet 338: 528–532, 1991

    PubMed  CAS  Google Scholar 

  • Patrick AW, Campbell IW. Fatal hypoglycaemia in insulin-treated diabetes mellitus: clinical features and neuropathological changes. Diabetic Medicine 7: 349–354, 1990

    PubMed  CAS  Google Scholar 

  • Patrick AW, Collier A, Hepburn DA, Steedman DJ, Clarke BF, et al. Comparison of intramuscular glucagon and intravenous dextrose in the treatment of hypoglycaemic coma in an accident and emergency department. Archives of Emergency Medicine 7: 73–77, 1990

    PubMed  CAS  Google Scholar 

  • Peacock I, Tattersall RD, Taylor A, Douglas CA, Reeves WG. Effects of new insulins on insulin and C-peptide antibodies, insulin dose and diabetic control. Lancet 1: 149–152, 1983

    PubMed  CAS  Google Scholar 

  • Perriello G, De Feo P, Torlone E, Calcinara F, Ventura MM, et al. Asymptomatic nocturnal hypoglycemia: a cause for deterioration of glycemic control in diabetes mellitus. New England Journal of Medicine 319: 1233–1239, 1988

    PubMed  CAS  Google Scholar 

  • Perriello G, De Feo P, Torlone E, Fanelli Santeusanio F, et al. Nocturnal spikes of growth hormone secretion cause the dawn phenomenon in Type 1 diabetes mellitus by decreasing hepatic (and extrahepatic) sensitivity to insulin in the absence of insulin waning. Diabetologia 33: 52–59, 1990

    PubMed  CAS  Google Scholar 

  • Pickup JC, Bilous RW, Viberti GC, Keen H, Jarrett RJ, et al. Plasma insulin and C-peptide after subcutaneous and intravenous administration of human insulin (recombinant DNA) and purified porcine insulin in healthy men. Diabetes Care 5(Suppl. 2): 29–34, 1982

    PubMed  CAS  Google Scholar 

  • Polonsky KS, Bergenstal RM, Pons G, Schneider M, Jaspan JB, et al. Relation of counterregulatory responses to hypoglycemia in type 1 diabetics. New England Journal of Medicine 307: 1106–1112, 1982

    PubMed  CAS  Google Scholar 

  • Polonsky KS, Herold Kgilden JL, Bergenstal RM, Fang VS, et al. Glucose counterregulation in patients after pancreatectomy: comparison with other forms of diabetes. Diabetes 33: 1112–1119, 1984

    PubMed  CAS  Google Scholar 

  • Potter J, Clarke P, Gale EAM, Dave SH, Tattersall RB. Insulin induced hypoglycaemia in an accident and emergency department: the tip of the iceberg. British Medical Journal 285: 1180–1182, 1982

    PubMed  CAS  Google Scholar 

  • Pramming S, Thorsteinsson B, Bendtson I, Binder C. Symptomatic hypoglycaemia in 411 Type 1 diabetic patients. Diabetic Medicine 8: 217–222, 1991

    PubMed  CAS  Google Scholar 

  • Pramming S, Thorsteinsson B, Bendtson I, Ronn B, Binder C. Nocturnal hypoglycaemia in patients receiving conventional treatment with insulin. British Medical Journal 291: 376–379, 1985

    PubMed  CAS  Google Scholar 

  • Pramming S, Thorsteinsson B, Theilgaard A, Pinner EM, Binder Cognitive function during hypoglycaemia in Type 1 diabetes. British Medical Journal 292: 647–650, 1986

    PubMed  CAS  Google Scholar 

  • Reeves WG, Allen BR, Tattersall RB. Insulin-induced lipoatrophy: evidence for an immune pathogenesis. British Medical Journal 280: 1500–1503, 1980

    PubMed  CAS  Google Scholar 

  • Rovet JF, Ehrlich RM, Hoppe M. Specific intellectual deficits in children with early onset diabetes mellitus. Child Development 59: 226–234, 1988

    PubMed  CAS  Google Scholar 

  • Ryder REJ, Owens DR, Hayes TM, Ghatei MA, Bloom SR. Unawareness of hypoglycaemia and inadequate hypoglycaemic counterregulation: no causal relation with diabetic autonomic neuropathy. British Medical Journal 301: 783–787, 1990

    PubMed  CAS  Google Scholar 

  • Sane T, Helve E, Pelkonen R, Koivisto VA. The adjustment of diet and insulin dose during long-term endurance exercise in Type 1 (insulin-dependent) diabetic men. Diabetologia 31: 35–40, 1988

    PubMed  CAS  Google Scholar 

  • Schluter KJ, Petersen K-G, Sontheimer J, Enzmann F, Kerp L. Different counter-regulatory responses to human insulin (recombinant DNA) and purified pork insulin. Diabetes Care 5(Suppl. 2): 78–81, 1982

    PubMed  Google Scholar 

  • Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for activation of glucose counterregulatory systems are higher than the threshold for symptoms. Journal of Clinical Investigation 79: 777–781, 1987

    PubMed  CAS  Google Scholar 

  • Shipp JC, Delcher HK, Munroe JF. Treatment of insulin hypoglycemia in diabetic campers: a comparison of glucagon (1 and 2 mg) and glucose. Diabetes 13: 645–648, 1964

    PubMed  CAS  Google Scholar 

  • Simonson DC, Tamborlane WV, DeFronzo RA, Sherwin RS. Intensive insulin therapy reduces counter-regulatory hormone responses to hypoglycemia in patients with Type 1 diabetes. Annals of Internal Medicine 103: 184–190, 1985

    PubMed  CAS  Google Scholar 

  • Slama G, Alamowitch C, Desplanque N, Letanoux M, Zirinis P. A new non-invasive method for treating insulin-reaction: intra nasal lyophylised glucagon. Diabetologia 33: 671–674, 1990b

    PubMed  CAS  Google Scholar 

  • Slama G, Traynard PY, Desplanque N, Pudar H, Dhunputh I, et al. The search for an optimized treatment of hypoglycaemia. Carbohydrates in tablets, solution, or gel for the correction of insulin reactions. Archives of Internal Medicine 150: 589–593, 1990a

    PubMed  CAS  Google Scholar 

  • Smith U, Blohme G, Lager I, Lonroth P. Can insulin-treated diabetics be given beta-adrenergic blocking drugs? British Medical Journal 281: 1143–1144, 1980

    PubMed  CAS  Google Scholar 

  • Soltesz G, Acsadi G. Association between diabetes, severe hypoglycaemia, and electroencephalographic abnormalities. Archives of Disease in Childhood 64: 992–996, 1989

    PubMed  CAS  Google Scholar 

  • Steel JM, Allwinkle J, Moffat R, Carrington DJ. Use of Lucozade and glucagon by ambulance staff for treating hypoglycaemia. British Medical Journal 304: 1283–1284, 1992

    PubMed  CAS  Google Scholar 

  • Sussman KE, Crout JR, Marble A. Failure of warning in insulin-induced hypoglycemie reactions. Diabetes 12: 38–45, 1963

    PubMed  CAS  Google Scholar 

  • Susstrunk H, Morell B, Ziegler WH, Froesch ER. Insulin absorption from the abdomen and thigh in healthy subjects during rest and exercise: blood glucose, plasma insulin, growth hormone, adrenaline and noradrenaline levels. Diabetologia 22: 171–174, 1982

    PubMed  CAS  Google Scholar 

  • Tattersall RB, Gill GV. Unexplained deaths of Type 1 diabetic patients. Diabetic Medicine 8: 49–58, 1991

    PubMed  CAS  Google Scholar 

  • Teuscher A, Berger WG. Hypoglycaemia unawareness in diabetics transferred from beef/porcine to human insulin. Lancet 2: 382–385, 1987

    PubMed  CAS  Google Scholar 

  • Thorsteinsson B, Pramming S, Lauritzen T, Binder Frequency of daytime biochemical hypoglycaemia in insulin-treated diabetic patients: relation to daily mean blood glucose concentrations. Diabetic Medicine 3: 147–151, 1986

    PubMed  CAS  Google Scholar 

  • Tunbridge WMG. Factors contributing to deaths of diabetics under 50 years. Lancet 2: 569–572, 1981

    PubMed  CAS  Google Scholar 

  • Whincup G, Milner RDG. Prediction and management of nocturnal hypoglycaemia in diabetes. Archives of Disease in Childhood 62: 333–337, 1987

    PubMed  CAS  Google Scholar 

  • White NH, Skor DA, Cryer PE, Levandoski LA, Bier DM, et al. Identification of type 1 diabetic patients at increased risk for hypoglycemia during intensive therapy. New England Journal of Medicine 308: 485–491, 1983

    PubMed  CAS  Google Scholar 

  • Widom B, Simonson DC. Glycemie control and neuropsychologic function during hypoglycemia in patients with insulin-dependent diabetes mellitus. Annals of Internal Medicine 112: 904–912, 1990

    PubMed  CAS  Google Scholar 

  • Williams JR. A clinical study of the effects of insulin in severe diabetes. Journal of Metabolic Research 2: 729–751, 1922

    CAS  Google Scholar 

  • Wright AD, Walsh CH, Fitzgerald MG, Malins JM. Very pure porcine insulin in clinical practice. British Medical Journal 1: 25–27, 1979

    PubMed  CAS  Google Scholar 

  • Young RJ, Hannan WJ, Frier BM, Steel JM, Duncan LJP. Diabetic lipohypertrophy delays insulin absorption. Diabetes Care 7: 479–480, 1984

    PubMed  CAS  Google Scholar 

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  1. Department of Medicine, Royal Liverpool University Hospital, PO Box 147, Liverpool, L69 3BX, England

    Alan W. Patrick & Gareth Williams

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  1. Alan W. Patrick
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  2. Gareth Williams
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Patrick, A.W., Williams, G. Adverse Effects of Exogenous Insulin. Drug-Safety 8, 427–444 (1993). https://doi.org/10.2165/00002018-199308060-00004

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