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The Real Science of Hypoglycemia PART 2

Although hypoglycemia affects both types of diabetics, episodes are much more common and frequent in Type I diabetics.
Untitled Document Hypoglycemia causes the body to respond with number of counterregulatory hormones.[i] [ii] Their most likely sequence of hormonal activation are glucagon, epinephrine and then if hypoglycemia is severe or prolonged cortisol and growth hormone.[iii] [iv]

The first, glucagon is a hormone produced in the alpha cells in the pancreas. When secreted it will activate a release of stored sugar in the form of glycogen, which is converted to glucose through a process called glucogenesis or glycogenolysis raising blood sugar.[v]

The next is epinephrine; it acts through similar pathways to elevate glucose levels through increased hepatic glucose production, gluconeogenesis, and also through decreased insulin secretion and glucose disposal.[vi] [vii] There is a release of another hormone related to epinephrine called norepinephrine.[viii] They both function as vasoconstrictors increasing blood pressure, cardiac output, and diverting blood flow from the extremities to the brain and major organs.[ix] [x] [xi] [xii] This vasoconstrictive effect may be more profound in diabetics with even a mild degree of nephropathy.[xiii] These aforementioned conditions may also be associated with a decrease in surface body temperature.[xiv] [xv]

The remaining two, cortisol and growth hormone work more on the level of reducing glucose uptake thus increasing blood sugar.[xvi] [xvii] Most of the time these defense mechanism do not engage soon enough to prevent the hypoglycemia from occurring due to some of type defect that seems to be more common in Type I diabetes.[xviii] [xix]

It appears that the glucagon release is delayed and possibly reduced from impaired alpha cell release.[xx] [xxi] This effect may be even more prominent in children with Type I diabetes.[xxii] This may be partially explained from the result of collateral damage caused by the autoimmune attack that effects the beta cells in the same islet in Type I diabetes.[xxiii] These hormone releases continue to increase blood glucose till it plateaus anywhere between two to eight hours after the event causing hyperglycemia, but it could last longer depending on several factors that will be explored.

This is called the Somogyi effect, post hypoglycemia hyperglycemia.[xxiv] These rebounds, as they are also referred to as, can happen anytime blood glucose drops below 70mg/dl and are usually responsible for wide swings in blood sugar levels.

In some diabetics, even before any type of hypoglycemic symptoms are experienced, counterregulatory hormones may already be activated. There are several variables that can effect hypoglycemic awareness such as actual postural position or intensive insulin therapy. Almost any angle of a reclined position will begin to decrease hypoglycemic awareness.[xxv] Also, studies show that the threshold required for hormonal release and hypoglycemic detection can be altered by tight glycemic control.[xxvi] Continued hypoglycemic incidents can decrease awareness, but this can be corrected through the elimination or reduction of hypoglycemic episodes.

There is some evidence that suggests that depending on how far blood sugar falls below 70mg/dl there is an inversely proportional amount of counterregulartory response.[xxvii] [xxviii] Glucagon and epinephrine usually begin to get released between 65-70mg/dl, while growth hormone and cortisol require slightly lower values from 55-65mg/dl.[xxix]

As blood sugar falls more tiers get activated, so the lower and possibly longer the blood sugar remains at that level the higher the blood sugar rebound value will be. There are other studies eluding to a recalibration of the response curve of counterregulartory hormones from tight blood glucose control that frequently causes blood sugar values to fall between 50 to 65mg/dl.[xxx] This seems to allow for a lower threshold to be reached in hypoglycemic incidents before a hormone release is initiated.[xxxi]

Sometimes counter regulatory hormones can be stimulated by a dramatic decrease in blood sugar occurring within a very short period of time.[xxxii] For this situation to occur it will usually require a drop of several hundred points in less than an hour to a fasting value. This can happen from the result of several different scenarios, but a combination of a large insulin injection and exercise might be the most common.

There may also be an opportunity to reduce or even avert a full counterregulartory response caused by hypoglycemia. There is a window that might remain open possibly up to 30 minutes from the time blood sugar drops below the threshold till glucagon is released.

If the hypoglycemia is detected and immediately addressed with one or several potential glucagon inhibitors the rebound could be curtailed. Although there are a number of different types of inhibiting agents, most of them are prescription drugs and hormones, which are not practical to use. Insulin and somatostatin are very potent inhibitors of glucagon, but they can only be delivered through injection and it is also not realistic to give someone suffering from hypoglycemia more insulin. The uses of somatostatin, which does have some benefits, could hinder the recovery process.[xxxiii] The few that might be of benefit and can be used on a repeated basis are calcium, magnesium, ibuprofen and antihistamines.[xxxiv] [xxxv] [xxxvi]

Any of these inhibitors can be used alone or in combination with each other. They can and should be given with the dose of 10-40 grams of carbohydrate as needed to correct the hypoglycemia.

Usually the detection and treatment for hypoglycemia are both symptom driven. To expedite recovery I suggest that you first use designated sports drink and then a carbohydrate with no fat. While sports drinks do not have the most sugar as compared to regular soft drinks or fruit juice, they have a faster transport mechanism that should speed hypoglycemic recovery. Large amounts of fat will just slow carbohydrate absorption hindering blood sugar rise. Normally, slowed uptake of carbohydrates has the benefit of better overall blood glucose profiles, but not during hypoglycemic treatment. Of all the times for hypoglycemia to occur one of the most dangerous is during the night. Nocturnal hypoglycemia usually gives no warning and counterregulatory recovery may be decreased during sleep, which can allow blood glucose to fall farther from the norms, so the risk for a person to go into shock increases.[xxxvii] This happens when glucose levels are to low for brain functions to operate properly. The brain has no glucose reserves to draw on directly and is more sensitive to low glucose levels than other organs. Temporary cognitive impairment can even begin when blood glucose is between 50-60 mg/dl and then deteriorates dramatically as blood glucose declines.[xxxviii] [xxxix] This is corrected when blood glucose is returned to normal.

There doesn't appear to be, but yet it is still unknown if these mild episodes cause any permanent brain damage, however they might hinder brain development in young children. However, severe hypoglycemia to the point of seizure or coma in children is associated with significant neurological abnormalities.[xl] These types of cases usually involve repeated professional medical intervention to recover from these hypoglycemic incidents.

The longer and lower the blood glucose remains, the greater the risk of multiple serious adverse effects. It is somewhat ironic that in the attempt to prevent complications from hyperglycemia you might cause other damage due to hypoglycemia of tight blood sugar control. Even though this fine balancing act may never be completely mastered, with the identification of the subtleties of your patient’s diabetes, these dangerous situations can be avoided or at least reduced. Click here for references

Dr. Brian P. Jakes, Jr., N.D., C.N.C. is a Board Certified Doctor of Naturopathy as well as a Certified Nutritional Consultant. In his practice, in Mandeville, LA, Dr. Jakes works with physicians to treat a large number of diabetes patients. This is an excerpt from his upcoming book; "Diabetes: The Essence Of A Cure”




[i] Lager I. The insulin-antagonistic effect of the counterregulatory hormones. J Intern Med Suppl 1991;735:41-7.

[ii] Bolli G, Gottesman I, Cryer P, Gerich J. Glucose counterregulation during prolonged hypoglycemia in normal man. Am J Physiol 1984;247:E206-14.

[iii] Gerich JE. Lilly lecture 1988. Glucose counterregulation and its impact on diabetes mellitus. Diabetes 1988 Dec;37(12):1608-17.

[iv] Cryer PE. Role of growth hormone in glucose counterregulation. Horm Res 1996;46(4-5):192-4.

[v] LeCavalier L, Bolli G, Cryer P, Gerich J. Contributions of gluconeogenesis and glycogenolysis during glucose counterregulation in normal humans. Am J Physiol 1989;256:E844-51.

[vi] Clutter WE, Rizza RA, Gerich JE, Cryer PE. Regulation of glucose metabolism by sympathochromaffin catecholamines. Diabetes Metab Rev 1988;4:1-15.

[vii] Cryer PE, Tse TF, Clutter WE, Shah SE. Roles of glucagon and epinephrine in hypoglycemic and non-hypoglycemic glucose counterregulation in humans. Am J Physiol 1984;247:E198-205.

[viii] Hoffman RP, Sinkey CA, Anderson EA. Hypoglycemic symptom variation is related to epinephrine and not peripheral muscle sympathetic nerve response. J Diabetes Complications 1997 Jan-Feb;11(1):15-20.

[ix] Neil HA, Gale EA, Hamilton SJ, Lopez-Espinoza I, Kaura R. Cerebral blood flow increases during insulin-induced hypoglycaemia in type 1 (insulin-dependent) diabetic patients and control subjects. Diabetologia 1987 May;30(5):305-9.

[x] Kerr D, Stanley JC, Barron M, Thomas R, et al. Symmetry of cerebral blood flow and cognitive responses to hypoglycaemia in humans. Diabetologia 1993 Jan;36(1):73-8.

[xi] Braatvedt GD, Newrick PG, Halliwell M, Wells PN, et al. Splanchnic haemodynamic changes during acute hypoglycaemia in man. Clin Sci (Colch) 1991 Oct;81(4):519-24.

[xii] Mathiesen ER, Hilsted J, Feldt-Rasmussen B, Bonde-Petersen F, et al. The effect of metabolic control on hemodynamics in short-term insulin-dependent diabetic patients. Diabetes 1985 Dec;34(12):1301-5.

[xiii] Bodmer CW, Patrick AW, How TV, Williams G. Exaggerated sensitivity to NE-induced vasoconstriction in IDDM patients with microalbuminuria. Possible etiology and diagnostic implications. Diabetes 1992 Feb;41(2):209-14.

[xiv] Maggs DG, Scott AR, MacDonald IA. Thermoregulatory responses to hyperinsulinemic hypoglycemia and euglycemia in humans. Am J Physiol 1994 Nov;267(5 Pt 2):R1266-72.

[xv] Wiles PG, Grant PJ, Stickland MH, Dean HG, Wales JK, Davies JA. Regional variation in skin blood flow response to hypoglycaemia in type 1 (insulin-dependent) diabetic patients without complications. Diabetologia 1988 Feb;31(2):98-102.

[xvi] Campbell IW. The Somogyi phenomenon. A short review. Acta Diabetol Lat 1976 Jan-Apr;13(1-2):68-73.

[xvii] DeFeo P, Perriello G, Torlone E, et al. Demonstration of a role for growth hormone in glucose counterregulation. Am J Physiol 1989;256:E835-43.

[xviii] Boli G, De Feo P, Compagnucci P. Abnormal glucose counterregulation in insulin dependent diabetes mellitus: interactions of anti-insulin antibodies and impaired glucagon and epinephrine secretion. Diabetes 1983; 32: 134-41.

[xix] Boli G, Calabrese G, De Feo P, Zega G. Lack of glucagon response in glucose counter-regulation in type 1 diabetics: absence of recovery after prolonged optimal insulin therapy. Diabetologia 1982 Feb;22(2):100-5.

[xx] Kleinbaum J, Shamoon H. Impaired counterregulation of hypoglycemia in insulin dependent diabetes mellitus. Diabetes 1983 Jun;32(6):493-8.

[xxi] Unger RH, Aguilar-Parada E, Muller WA, Eisentraut AM. Studies of pancreatic alpha cell function in normal and diabetic subjects. J Clin Invest 1970;49:837-48.

[xxii] Hoffman RP, Arslanian S, Drash AL, Becker DJ. Impaired counterregulatory hormone responses to hypoglycemia in children and adolescents with new onset IDDM. J Pediatr Endocrinol 1994 Jul-Sep;7(3):235-44.

[xxiii] Taborsky GJ, Ahren B, Havel P. Autonomic mediation of glucagon secretion during hypoglycemia: implications for impaired alpha-cell responses in type 1 diabetes. Diabetes, July 1998 v47 n7 p995(11).

[xxiv] Somogyi M. Exacerbation of diabetes by excess insulin action. Am J Med 1959;26:169-91.

[xxv] Robinsion AM, Parkin HM, Macdonald IA, Tattersall RB. Physiological response to postural change during mild hypoglycaemia in patients with IDDM. Diabetologia 1994 Dec;37(12):1241-50.

[xxvi] Dagogo-Jack S, Rattarasarn C, Cryer PE. Reversal of hypoglycemia unawareness, but not defective glucose counterregulation, in IDDM. Diabetes 1994 Dec;43(12):1426-34.

[xxvii] Lewis GF, Carpentier A, Bilinski D, Giacca A, Vranic M. Counterregulatory response to hypoglycemia differs according to the insulin delivery route, but does not affect glucose production in normal humans. J Clin Endocrinol Metab 1999 Mar;84(3):1037-46.

[xxviii] Kerr D, MacDonald IA, Tattersall RB. Influence of duration of hypoglycemia on the hormonal counterregulatory response in normal subjects. J Clin Endocrinol Metab 1989;68:1118-22.

[xxix] Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for activation of glucose counterregulatory systems are higher than threshold for symptoms. J Clin Invest 1987 Mar;79(3):777-81.

[xxx] Simonson DC, Tamborlane WV, DeFronzo RA, Sherwin RS. Intensive insulin therapy reduces counterregulatory hormone responses to hypoglycemia in patients with type 1 diabetes. Ann Intern Med 1985 Aug;103(2):184-90.

[xxxi] Davis M, Mellman M, Friedman S, et al. Recovery of epinephrine response but not hypoglycemic symptom threshold after intensive therapy in type I diabetes. Am J Med, Dec 1994 v97 n6 p535(8).

[xxxii] DeFronzo RA, Andres R, Bledsoe TA, et al. A test of the hypothesis that the rate of fall in glucose concentration triggers counterregulatory hormonal responses in man. Diabetes 1977;26:445-52.

[xxxiii] Gerich JE, Davis J, Lorenzi M, et al. Hormonal mechanisms of recovery from insulin induced hypoglycemia in man. Am J Physiol 1979;236:E380-5.

[xxxiv] Cucinotta D, Quartarone M, Saitta A, De Pasquale R, Perdichizzi G, Squadrito G. Calcium and endocrine pancreas secretion. I. Effects of an infusion of calcium on plasma levels of insulin and glucagon. Boll Soc Ital Biol Sper 1980 Feb 29;56(4):332-8.

[xxxv] Leclercq-Meyer V, Marchand J, Malaisse WJ. The role of calcium in glucagon release. Interactions between arginine and calcium. Horm Res 1976;7(6):348-62.

[xxxvi] Giugliano D, Torella R, D’Onofrio F. Prostaglandins and the alpha cell. Prostaglandins Med 1981 Mar;6(3):283-7.

[xxxvii] Jones TW, Porter P, Sherwin RS, Davis EA, et al. Decreased epinephrine responses to hypoglycemia during sleep. N Engl J Med 1998;338:1657-62.

[xxxviii] Gold AE, MacLeod KM, Deary IJ, Frier BM. Hypoglycemia-induced cognitive dysfunction in diabetes mellitus: effect of hypoglycemia unawareness. Physiol Behav 1995 Sep;58(3):501-11.

[xxxix] Gschwend S, Ryan C, Atchison J, Arsianian S, Becker D. Effects of acute hyperglycemia on mental efficiency and counterregulatory hormone in adolescents with insulin-dependent diabetes mellitus. J Pediatr 1995 Feb;126(2):178-84.

[xl] Ingram TTS, Stark GD, Blackburn I. Ataxia and other neurological disorders as sequels of severe hypoglycemia in childhood. Brain 1967;90:851-62.



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This article originally posted 02 July, 2004 and appeared in

Past five issues: Diabetes Clinical Mastery Series Issue #248 | Issue 788 | Diabetes Clinical Mastery Series Issue 247 | Issue 787 | Diabetes Clinical Mastery Series Issue 246 |

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