A Glimpse of Journey through Low Blood Glucose
*Dr. Biswajit Saha
Hypoglycaemia is a common complication in the management of diabetes mellitus. The importance of this condition is that once the diagnosis is suspected, confirmation takes minimum time now-a-days and a life can be saved from a dire medical emergency regardless of its cause by one of the simplest and cheapest method of treatment – administer glucose orally, if required, followed by carbohydrate containing meal or intravenously if the patient is unconscious or rarely, with intramuscular injection of glucagon. A brief account on hypoglycaemia is given followed by some of my experiences.
During fasting conditions, normally plasma glucose is maintained within a relatively narrow range of 70-110 mg/dl by endogenous glucose production through hepatic glycogenolysis, hepatic and renal gluconeogenesis. After a meal, despite variations in exogenous glucose delivery, there is transient higher excursion of blood glucose to around 150-160 mg/dl but by a very complex yet balanced integrated mechanism involving critical interplay of release of hormones and their actions on key metabolic pathways, resulting in smooth transition of blood glucose level normally from a transiently elevated glucose influx from meal or glucose to a basal level after 2 -3 hrs or so. However, as the plasma glucose level falls to around 80-85 mg/dl, the release of insulin from pancreatic beta cell decrease which is the first defense in glucose counterregulation. This causes increase in glycogenolysis and neoglucogenesis, reduction in peripheral glucose utilization and induction of lipolysis including proteolysis thereby, releasing gluconeogenic precursors. As the plasma glucose levels decline just below the physiological range, glucose elevating hormones are released. Among these, the second defense, pancreatic α-cell glucagon which stimulates hepatic glycogenolysis plays a primary role. Adrenomedullary epinephrine which stimulates glycogenolysis and neoglucogenesis becomes particularly critical when glucagon is deficient. Epinephrine is the 3rd defense against hypoglycaemia. When hypoglycaemia is prolonged, cortisol and growth hormone also support glucose production and limit glucose utilization. With these hormonal responses, symptoms prompt ingestion of food.
Although the following symptoms have been described, most of the diabetic patients usually do not have those and in day-to-day practice, it is learnt that they can “sense” low blood ‘sugar’ – with somewhat uneasiness which passes off after eating some amount of glucose/ sugar/ sweets and taking rest. The symptoms of hypoglycaemia are adrenergic symptoms like palpitation, tremor, anxiety mediated largely by nor epinephrine released from sympathetic postganglionic neurons but perhaps also by epinephrine released from the adrenal medullae and/or cholinergic symptoms like sweating, hunger, paresthesia etc. mediated by acetylcholine released from sympathetic postganglionic neurons. Glucose is an obligate metabolic fuel for the brain under physiological conditions. Neuroglycopenic symptoms are the direct result of glucose deprivation to the brain. These include behavioural change, confusion, fatigue, seizure, loss of consciousness and if hypoglycaemia is severe and prolonged, death is likely. However, these warning symptoms of hypoglycaemia are not appreciated when there is defective glucose counterregulation or hypoglycaemia unawareness. This means that the patient may not have any symptoms although blood glucose is low. Clinically, the differentiation from hyperglycaemia is made by a suggestive history alongwith shallow or normal respiration, clammy and sweating skin, moist tongue, full pulse volume, normal or raised blood pressure and brisk reflexes. Glycaemic threshold is the blood glucose level at which counter regulatory mechanism starts operating. It is essentially a metabolic set point of an individual’s glucose homeostasis. This is dynamic i.e. it changes from time to time in the same individual. Normally, the counterregulation starts at around 80-85 mg/dl. However, if attempt is made to bring down the blood glucose level particularly aggressively to a normal level from a chronically elevated level in a poorly controlled diabetic, the patient might experience hypoglycaemic symptoms at a higher-than-normal. This is known as “relative hypoglycaemia”. I have noted this occurring usually in the aged and also educated, particularly internet–savvy individuals. The reverse, i.e. shifting to lower-than-normal is also possible as a result of recurrent attacks of hypoglycaemia. Again, this shifting to the lower side causes hypoglycaemic symptoms occurring at a lower level than conventionally known.
Hypoglycaemia is the main limiting factor in diabetes management which involves three things – diet (quantity, quality & timings), exercise (degree & duration) and anti diabetic drugs (oral /insulin – doses, drug interaction) . Depending on the clinical conditions, these are adjusted to get the desired glycaemic goals in an individual. Any overadjustment of the three either alone or in combination is tantamount to “overadministration” and is the cause of hypoglycaemia. For example, while keeping exercise and antidiabetic drugs (particularly insulin) fixed, if an individual tries to decrease the quantity/quality of food or inappropriately alter the timing of intake, the patient is likely to have hypoglycaemia. Similarly, in Insulin dependent diabetic, aggressive exercise and particularly timing of taking insulin injection if not appropriate with the food intake, hypoglycaemia is likely. The patient should be educated about this.
Although there are many causes, hypoglycaemia is most commonly caused by drugs used to treat diabetes particularly insulin and sulfonylureas. Among the causes of postprandial hypoglycaemia, postgastrectomy or gastrojejunostomy is common,
Do we really know what is the consensus lower limit of normal fasting plasma glucose level ? It is well-known that reference range of a geographical area is to be established as per its population. I do not know whether anybody is really adopting it. India is vast country with a variety of people in different regions. It is really difficult to have a consensus level. Despite requests and pressures, we report the level only without any reference range because of not only the above and following issues but also desired glycaemic goals for an individual patient. It is not known to me the sources of reference range as reported by many laboratories but seemingly, the source being reagent literatures. Clinicians usually follow the levels mentioned in the text books or most commonly, the guidelines issued from time to time with changing figures by the internationally accepted agencies like American Diabetes Association (ADA). Regarding normal levels of fasting plasma glucose, the following references may be looked into1-8.
Plasma Glucose (mg/dl)
Text Books:
Harrison’s Medicine (17th ed), 2008 70* (75 -110)
API Text Book of Medicine (8th ed),2008 NA#
Davidson’s Medicine (20th ed), 2006 64 -104
Tietz Clinical Chemistry (4th ed) 2006 74 – 100
Harrison’s Medicine (16th ed), 2005 75 -115
(* Mentioned in the chapter on Hypoglycaemia, # No figure against only glucose level but levels of other parameters available in the table at the end of the book)
Reagent Literature
Olympus 74 - 100
Roche 70 - 115
Diasys 70 - 115
Accurex 60 - 110
Pvt. Laboratories
Dr. Lal’s Path Lab Pvt Ltd, N. Delhi 70 - 110
Metropolis Health Services (India) Ltd, Mumbai 70 - 100
International Authority
American Diabetes Association (2006/2009) < 100*
(lower limit ?)
(* ADA 2010 guidelines indirectly mention the same level)
Since there is no grey zone between the lower limit of normal level and hypoglycaemia, would it be rational to consider any level lower than lower limit of normal level as hypoglycaemia? What is the level for hypoglycaemia then? Again, regarding diagnosis of hypoglycaemia, the levels as mentioned in the following require to be noted1-9.
Plasma Glucose (mg/dl)
Harrison’s Medicine (16th ed), 2005 - <45 - 50
Harrison’s Medicine (17th ed), 2008 - <55
Davidson’s Medicine (20th ed), 2006 - <63
Williams Endocrinology, (11th ed), 2008 <54
API Text Book of Medicine (8th ed), 2008 <50
Tietz Clinical Chemistry (4th ed) 2006 50 / 60
American Diabetes Association (2006/2010) <70
However, plasma glucose level alone is not sufficient for the diagnosis. The patient must have i) symptoms consistent with hypoglycaemia, ii) simultaneous low plasma glucose concentration by a precise method, not by glucometer and iii) relief of symptoms after plasma glucose level is increased. This is known as “Whipple’s triad” which needs to be satisfied for the diagnosis. This means, low blood glucose i.e. biochemical hypoglycaemia is not synonymous with clinical hypoglycaemia.
Although it is known that after a glucose tolerance test (GTT), normally the blood glucose level at 2 hr is at or slightly below the fasting level. Yet there is a traditional concept that postprandial (PP) level should be higher than fasting(F)! Accordingly, a PP value slightly higher than F is well accepted. After seeing a PP value lower than F, particularly if the difference is remarkable, the first reaction by the treating doctor that the report is wrong! I have been hearing from the patients that the reactions range from usually smiling, frowning, laughing to even tearing the report in anger, at times, so badly that a sense of incredibility about the laboratory is impregnated into the psyche of the patients. I feel it should be a rational approach to investigate into the case in detail rather than blaming the laboratory at the very outset.
Primarily due to constraints of the size of the article, now, only a few cases as observed by me since 1992 have been described in a somewhat small story form. Although conventionally still “Blood Sugar” is advised by the doctors, technically, the correct terminology is “plasma glucose” since perhaps almost all laboratories have been measuring plasma glucose unlike previously. The analysis was done by the state-of-the-art autoanalyzers, Hitachi 704 and Olympus AU 400 /640 autoanalyzers with stringent quality control. All these levels were at least rechecked - at times, reconfirmed after serial dilutions to rule out any analytical error before final reporting.
Case 1 (1994): A 44 yrs male (our hospital attendant) came for routine “blood sugar” checking in the OPD. Report - F – 99 mg/dl, PP (post glucose, PG) – 42 mg /dl. After noting PP level at 2 hr remarkably lower than fasting, PP was repeated after 10 days – almost same result – 44mg/dl. There was no symptom. The patient was requested to undergo an extended GTT after 12 days.
F ½ hr 1hr 1½hr 2hr 2½hr 3hr 3½hr 4hr
Plasma Glucose 100 243 191 81 53 64 69 82 87
(mg/dl)
There is an abrupt increase at ½ hr, then remarkably low at 2 hrs, then again rising. Neither there was anything written against diagnosis in the Investigation Requisition nor the patient disclosed anything. Otherwise, the extended GTT would not have been done. Being curious, after going through his medical booklet, it was known that the patient had a vagotomy with gastrojunostomy 10 yrs back. The sudden increase at ½ hr is due to rapid delivery of glucose directly to jejunum bypassing pyloric sphincter and duodenum. The subsequent lowering is due to release of gut incretin which induce an exuberant insulin response. This is a well known cause of PP hypoglycaemia
Case 2 (1995): 25 yrs old married female came for “blood sugar” testing. Initial routine investigation showed a remarkably low PP plasma glucose of 53 mg/dl compared to a F level of 85 mg/dl. GTT was done.
F ½ hr 1 hr 1½hr 2hr 2½hr
Plasma Glucose 85 131 114 55 73 31
(mg/dl)
GTT showed similar figure at 1½ hr and 31 at 2 ½ hr. Even at this low level there was no symptom. The patient was willing to undergo an extended GTT done a week later.
F ½ hr 1hr 1½hr 2hr 2½hr 3hr 3½hr 4hr 4 ½ hr
Plasma Glucose 95 137 47 72 115 71 68 65 90 97
(mg/dl)
Considering her age and marital status, I thought that she was doing a routine antenatal check up for investigation. Later, I learnt that she had three spontaneous abortions
Case 3 (1995): This a case of 49 yrs female who again showed a remarkably low PP of 40 mg/dl without any symptom. She got a PP done from a private laboratory with a level of 115 mg/dl and challenged our result. On enquiry, I came to know that the investigation was done after a meal and not after glucose. The patient came prepared after taking a meal for reconfirmation. PP was done and found to be 108 mg/dl. I convinced the patient to undergo an Extended GTT which she agreed.
F ½ hr 1 hr 1½hr 2hr 2½hr 3hr 3½hr 4hr
Plasma Glucose 96 156 137 49 76 83 62 78 87
(mg/dl)
After seeing the result, I again convinced her to undergo an extended post meal tolerance test with her usual meal after one week.
F ½ hr 1hr 1½hr 2hr 2½hr 3hr 3½hr 4hr
Plasma Glucose 90 142 126 115 128 112 86 92 X
(mg/dl)
The difference of results between a standard glucose load (75 gms) and the patient’s usual meal (the traditional Bengali diet – rice, dal, vegetables and a piece of fish) in the same individual may be noted. There is remarkable lowering of PP level with glucose but not with usual meal - it is higher than fasting. This was an interesting observation for me in 1995. Over a period of 10 yrs, without having a proper explanation for the above much to the disappointment of the patients primarily due to nonexistence of any other relevant investigations facility like insulin, C-peptide, glucagons, epinephrine etc in our general industrial hospital, informed consents were obtained from 36 patients only. The results of this study was published10. The above case is not idiopathic reactive hypoglycaemia since PP level after mixed meal was higher than fasting. Glucose appears to be a stronger stimulus than usual meal in these individuals in causing remarkable lowering of PP levels. The following could be possible explanations – an unconventional intake of large amount of glucose (monosaccharide – a readily absorbable form) ingested is rapidly absorbed from the intestine seemingly with increased gastrointestinal (GI) motility as well in some individuals with altogether different hormonal and metabolic responses. In contrast, the GI system of an individual is habituated to a conventional mixed meal [carbohydrate (polysaccharides), fat, protein fibres etc], the composition of which largely determines the GI motility including rate of digestion and absorption thereafter. Obviously, this causes delay and consequently allows more natural responses unlike former.
Case 4 (1998): This a case known to me with longstanding diabetes mellitus on oral antidiabetic drug (glypizide). He was somewhat uneasy and could not adjust the gear of the car while returning from marketing in the morning but became normal after taking two “rasogolla”s. I asked him to come under identical condition on the very next day to the laboratory after taking breakfast and medicines as usual. One and two hr PP levels were 28 and 20 mg/dl respectively. These levels were not deliberately informed only to wait for the time of occurrence of the typical symptoms experienced on the preceding day. After taking a 3 hr sample and subjecting for immediate analysis, I escorted him walking for about 150 meters to a local sweet shop to take sweets. The level at 3hr was found to be 31 mg/dl only. The patient was normally talking and walking even at this low level. This indicates on the preceding day, the level would, presumably, be less than 20 mg/dl. After observing the patient for seven yrs, this case was published11.
Case 5 (1996): An known hypertensive and diabetic patient (60yrs female) had a plasma glucose level of 5 mg/dl despite remaining admitted in the hospital as a result of overadministration of antidiabetic regimen resulting from poor monitoring. However, the patient did not have any coma and fortunately, the case was diagnosed although a bit late and treated forthwith. Later, she was discharged after taking due care.
After 5 mg/dl was reported, I was severely criticized in our hospital. While searching for the lowest recorded level in the world literatures, I came across one paper describing symptomless hypoglycaemia with a blood glucose level of 7mg/dl only12.
When I wanted to get the above published as a “Case Report” in the Journal of Indian Medical Association (JIMA) in 2006, JIMA did not want to publish. When a copy of the “symptomless hypoglycaemia with 7 mg/dl” and my two above published papers were sent, JIMA accepted for publication13. This is a problem of publication of new finding(s) particularly in our own Indian journals. The acceptance of truth needs to inculcated by changing our mindset of ‘certification by foreign somebody’.
Case 6 (1997): One has to see this case to believe. Suicidal attempt was made by a 4th yr MBBS student (23yr,F) by consuming 40 tablets of 250 mg Chlorpropamide (her mother used to take the drug) – a long acting antidiabetic drug. She was found unconscious in the bathroom and brought to the hospital in a state of coma. 10% dextrose was transfused IV to which 25% dextrose was added as bolus in right forearm i.e. 35000 mg/dl glucose was running in circulation. Blood was drawn from left arm almost immediately after the bolus injection. Plasma glucose measured by autoanalyzer was only 5mg/dl. This indicated that the patient practically did not have any measurable amount (? “0” mg/dl) of glucose without exogenous glucose supplementation. Anyway, the patient survived, felt ashamed of her misconduct but despite requests did not come for follow up for any delayed neurological or neuropsychiatric complications.
Case 7 (2009): A 15 yr male was admitted with complaints of weakness, restlessness and increased appetite. Next morning, fasting plasma glucose level was 558 mg/dl . Insulin was started. Blood glucose normalized within 7 days and the patient was discharged. After 10 days, he had a remarkably low PP level of 37 mg/dl reconfirmed after 5 days – 33 mg/dl. There is a concept that recurrent hypoglycaemia lowers glycaemic threshold. In this case, the patient did not have any symptom (talking and walking normally) despite a recent drastic reduction with appreciable lowering of 33 mg/dl. After about a month, the patient once had a reeling sensation. Blood glucose estimated by his glucometer was found to be 28 mg/dl. This indicated that the patient could sense around a level of less than 30mg/dl.
To sum up the cases, it may be realized that with the remarkably low almost same level, one patient remains normal as usual without any problem while another dies. Patient recovered from practically “0” mg/dl level in the suicidal case. Casual/routine investigation revealed symptomless hypoglycaemia with 7 mg/dl in otherwise normal individual compels us to introspect a bit in detail. Theoretically, with progressively downward figures from 6,5,4,3,2,1 to even 0, it is flavergasting to think of the possibility symptomless hypoglycaemia including existence of life! What is limit ? These bewildering observations are really haunting and indeed enigmatic. It is appreciated that these are examples of some other hitherto unknown biochemical energy producing mechanism operating beyond our well-established concepts of so-called glycaemic threshold and nutrition to the brain. Hence, blood glucose level should not, prudently, be the only cause always for the clinical features in a given case. The main problem in all the above cases is of any hypoglycaemic symptom presumably due to defects in counterregulation or lowering of glycaemic threshold either as a primary disturbance in glucose metabolism with consequent lowering of metabolic set-point or secondarily from recurrent hypoglycaemia or most likely some other unknown cause(s). This is a real problematic issue both for the patient to take necessary actions in time and the treating doctor to adjust antidiabetic regimen. In a pragmatic way, it is felt that the glycaemic goals for such type of individuals (in whom the exact cause has not been elucidated with certainty) should be set at a slightly higher-than-desired level for obvious reasons explaining the same to the patient.
In conclusion, there is no clear cut lower limit of normal plasma glucose level unlike upper limit. The otherwise normal individual who exhibit remarkably lower PP (PG) plasma glucose than fasting show higher PP value than F if done with their traditional meal. There is no consensus plasma glucose level for diagnosing hypoglycaemia as well. Also, glycaemic threshold for hypoglycaemic symptoms varies unbelievably widely both in diabetic and non-diabetic individuals. In these perspectives, hypoglycaemia appears to be a confusing term since the “so-called biochemical hypoglycaemia” is not synonymous with “clinical hypoglycaemia”. Hence, the laboratory can not be blamed only because the clinical presentation does not match with the reported low level. Lastly, even if Whipple’s triad is not satisfied, pragmatically one must not ignore a remarkably low plasma glucose level in any individual.
References:
- Harrison’s Principles of Internal Medicine, 17th Ed, 2008 Eds Fauci Anthony S, Braunwald Eugene, Kasper Dannis L , Hauser Stephen L, Longo Dan L, Jameson J Larry and Loscalzo Joseph
- API Text Book of Medicine, 8th Ed, 2008, Editor-in-chief - Shah Siddharth N
- Davidson’s Principles and Practice of Medicine, 20th Ed, 2006, Eds Boon Nicholas A, Colledge Nicki R, Walker Brian R and Hunter John A A
- Tietz Text Book of Clinical Chemistry & Molecular Diagnostics, 2006, 4th Ed, Eds Burtis Carl A., Ashwood Edward R and Brians David E
- Harrison’s Principles of Internal Medicine, 16th Ed, 2005 Eds Kasper Dannis L, Braunwald Eugene, Fauci Anthony S, Hauser Stephen L, Longo Dan L and Jameson J Larry
- ADA 2006 Guidelines, Diabetes Care, Vol 29, Suppl 1, Jan 2006, s16 & s47
- ADA 2009 Guidelines, Diabetes Care, Vol 32, Suppl 1, Jan 2009, s27 & s66
- ADA 2010 Guidelines, Diabetes Care, Vol 33, Suppl 1, Jan 2010, s28 & s66
- Williams Text Book of Endocrinology ( 11th ed), 2008 Eds Kronenberg Henry M, Melmed Shlomo, Polonsky Kenneth S, and Larsen P Reed
- Saha B. 2006. Post prandial plasma glucose less than fasting in otherwise normal individuals during routine screening. IJCB, 21(2); 67-71
- Saha B. 2006. Ambulatory diabetic patient with remarkable hypoglycaemia. IJCB, 21(2); 189
- Andreason AT and Maraspini Christiana. 1976. Symptomless hypoglycaemia. S. Afr. Med. J, 50: 1331-1341
- Saha B. 2007. Hypoglycaemia without coma. JIMA, 105(02): 99
*Joint Director, Medical and Health Services, Durgapur Steel Plant Hospital
Durgapur, West Bengal
