Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set

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to health care (including acceptance of and use of

services). In some respects, unhealthy diet is a form

of malnutrition that afflicts poor people in developed

countries. The striking differences in diseases between

the socioeconomic classes, usually defined in terms of

educational level and income, are clearly environ-

mental rather than genetic in origin. Therefore,

there is much the society, through governmental and

nongovernmental agencies, can do to reverse this.

0021 A healthier diet brings many dividends – it reduces

calorie, sodium, cholesterol, and triglyceride intake

and increases the intake of potassium and calcium,

and the consumption of fruit and vegetables which

are rich in fiber and vitamins. Therefore, we should

strive to shift the dietary habit of the whole popula-

tion, including children and adolescents, as much as

patients with hypertension and other cardiovascular

conditions. A family rather than an individual ap-

proach is often called for if the family eats together.

The advantage of this is that the whole family can

start to adapt to a healthy diet. Primary prevention of

hypertension may then become a reality rather than

just a possibility.

See also: Alcohol: Properties and Determination;

Calcium: Properties and Determination; Physiology;

Hypertension: Physiology; Obesity: Etiology and

Diagnosis; Potassium: Properties and Determination;

Physiology; Sodium: Properties and Determination;

Physiology

Further Reading

Alderman MH (2000) Salt, blood pressure, and human

health. Hypertension 890–893.

Allender PS, Cutler JA, Follmann D et al. (1996) Dietary

calcium and blood pressure: a meta-analysis of random-

ized clinical trials. Annals of Internal Medicine 124:

825–831.

Appel LJ, Moore TJ, Obarzanek E et al. (1997) A clinical

trial of effects of dietary patterns on blood pressure:

DASH collaborative research group. New England

Journal of Medicine 336: 1117–1124.

Ascherio A, Hennekens CH, Willet WC et al. (1996) Pro-

spective study of nutritional factors, blood pressure,

and hypertension among US women. Hypertension 27:

1065–1072.

Ascherio A, Rimm EB, Givovannucci E et al. (1992) A

prospective study of nutritional factors and hypertension

among US men. Circulation 86: 1475–1484.

Barker DJP, Osmond C, Golding J, Kuh D and Wadsworth

MEJ. Growth in utero, blood pressure in childhood and

adult life, and mortality from cardiovascular disease.

British Medical Journal 298: 564–567.

Considine RV, Sinha MK, Heiman ML et al. (1996) Serum

immunoreactive leptin concentrations in normal-weight

and obese humans. New England Journal of Medicine

334: 292–295.

Fagard RH (1993) Physical fitness and blood pressure.

Journal of Hypertension 11 (suppl. 5): S47–S52.

Gillum RF, Mussolino ME and Madans JH (1998) Body fat

distribution and hypertension incidence in women and

men. The NHANES I epidemiologic follow-up study.

International Journal of Obesity Related Metabolic

Disorders 22: 127–34.

Hypertension Detection and Follow-up Program Coopera-

tive Group (1987) Educational level and 5-year all cause

mortality in the hypertension detection and follow-up

program. Hypertension 9: 641–646.

Intersalt Cooperative Research Group (1988) Intersalt:

an international study of electrolyte excretion and

blood pressure: results for 24-hour urinary sodium

and potassium excretion. British Medical Journal 297:

310–328.

Kotchen TA, McCarron DA for the Nutrition Committee

(1998) Dietary electrolytes and blood pressure. A state-

ment for healthcare professionals from the American

Heart Association Nutrition Committee. Circulation

98: 613–617.

Law MR, Frost CD and Wald NJ (1991) By how much does

dietary salt reduction lower blood pressure? British

Medical Journal 302: 811–824.

MacGregor GA and De Wardener HE (1998) Salt Diet and

Health. Cambridge: Cambridge University Press.

Pang PK, Shan JJ, Lewanczuk RZ and Benishin CG (1996)

Parathyroid hypertensive factor and intracellular cal-

cium regulation. Journal of Hypertension 14: 1053–

1060.

Poulter NR, Khaw KT, Hopwood BE et al. (1990) The

Kenyan Luo migration study: observations on the initi-

ation of a rise in blood pressure. British Medical Journal

300: 967–972.

Reaven GM, Lithell H and Landsberg L (1996) Hyperten-

sion and associated metabolic abnormalities. The role of

insulin resistance and the sympathoadrenal system. New

England Journal of Medicine 334: 374–381.

Sacks FM, Brown LE, Appel L et al. (1995) Combinations

of potassium, calcium, and magnesium supplements in

hypertension. Hypertension 26: 950–956.

Singhal A, Cole TJ and Lucas A (2001) Early nutrition in

preterm infants and later blood pressure: two cohorts

after randomised trials. Lancet 357: 413–419.

Stamler J, Caggiula A, Grandits GA, Kjelsberg M and

Cutler JA for the MRFIT Research Group (1996)

Relationship of blood pressure of combinations of

dietary macronutrients. Findings of the Multiple Risk

Factor Intervention Trial (MRFIT). Circulation 94:

2417–2423.

Whelton PK, He J, Cutler JA et al. (1997) Effects of oral

potassium on blood pressure: meta-analysis of random-

ized controlled clinical trials. Journal of the American

Medical Association 277: 1624–1632.

Whelton PK, Appel LJ, Espeland MA et al. (1998) TONE

Collaborative Research Group. Sodium reduction and

weight loss in the treatment of hypertension in older

persons: a randomized controlled trial of nonpharmaco-

logic interventions in the elderly (TONE). Journal of the

American Medical Association 279: 839–846.

HYPERTENSION/Hypertension and Diet 3199

Nutrition in the Diabetic

Hypertensive

S C Bain, University of Birmingham and Birmingham

Heartlands Hospital, Bordesley Green East,

Birmingham, UK

P M Dodson, Birmingham Heartlands Hospital,

Bordesley Green East, Birmingham, UK

Hypertension as a Secondary

Complication of Diabetes

0001 Diabetes mellitus and hypertension are frequently

associated: hypertension is approximately twice as

common in subjects with diabetes mellitus compared

with the general population. The prevalence of hyper-

tension increases with age and is relatively greater in

those with type 1 (insulin-dependent) diabetes than

in those with type 2 (noninsulin-dependent) diabetes

after adjustment for age. As in the general population,

hypertension occurs more frequently in diabetic

males than in diabetic females before the fifth decade

and more frequently in diabetic women thereafter.

0002 The etiology of hypertension in association with

diabetes is poorly understood and is probably differ-

ent in the two types of diabetes. Hypertension in type

1 diabetes is generally related to the development

of diabetic kidney damage (diabetic nephropathy)

which occurs in up to 40% of subjects. Diabetic

nephropathy may also occur in type 2 diabetes but is

less common (less than 20%). This form of hyperten-

sion may rightly be regarded as a secondary compli-

cation of diabetes.

0003 In contrast, the majority of type 2 diabetic subjects

with raised blood pressure have essential hyperten-

sion. This may be a consequence of the diabetic state

but is more likely to be an association due to a

common etiologic factor such as insulin resistance

(see below). Type 2 diabetic patients are also prone

to the development of isolated systolic hypertension

but other ‘secondary’ causes of hypertension do

not occur with increased frequency in the diabetic

population.

Factors Associated with Hypertension in

the Diabetic

Essential Hypertension

0004 The reported prevalence of essential hypertension

(previously defined as blood pressure more than

160/95 mmHg) among newly diagnosed type 2 dia-

betic patients is 40% in men and 53% in women.

This prevalence is age-related in both sexes, consist-

ently higher in women than in men, and greater than

seen in an age- and sex-matched healthy population.

Obesity explains part of the increased prevalence

since approximately 75% of type 2 diabetics are

overweight and obesity is independently associated

with raised blood pressure. However, the association

of type 2 diabetes and essential hypertension has yet

to be fully explained.

0005In 1988 Reaven introduced the term ‘Syndrome X’

to describe the cooccurrence of hypertension,

impaired glucose tolerance, dyslipidemia (raised tri-

glycerides, low high-density lipoprotein cholesterol),

hyperinsulinemia, and insulin resistance (Table 1). He

proposed this as a cardiovascular risk factor complex

and suggested that insulin resistance was causal in the

development of the other abnormalities in the syn-

drome. There are a number of potential mechanisms

by which insulin resistance, and the consequent

hyperinsulinemia, could induce hypertension. For

example, increased sodium retention, disturbed

sodium/potassium transport, and sympathetic ner-

vous system overactivity have all been reported.

Since obesity is a state of increased peripheral resist-

ance to insulin, this hypothesis provides an explan-

ation for the association of obesity with both type 2

diabetes and raised blood pressure.

0006Since its original description, Reaven’s syndrome

has continued to be the focus of much research and

has expanded to include postprandial hyperlipidemia,

the presence of small dense low-density lipoproteins,

hyperuricemia, and abnormal clotting factors. The

persistence of the syndrome implies that it is import-

ant; however, the causal mechanisms have yet to be

dissected and the precise role of insulin resistance

remains controversial.

0007The definition of hypertension is also a rapidly

changing area. Controlled clinical trials of drug inter-

vention now suggest that target levels for systolic and

diastolic blood pressure in patients with type 2 dia-

betes should be in the order of 140/85 mmHg. The

goals are lower if patients have known ischemic heart

disease (130 and 80 mmHg) and are lower still in

patients with type 1 diabetes and evidence of diabetic

tbl0001Table 1 Original components of Syndrome X (Reaven’s

syndrome)

Insulin resistance

Hyperinsulinemia

Impaired glucose tolerance

Raised triglycerides

Low HDL-cholesterol

Hypertension

HDL, high-density lipoprotein.

3200 HYPERTENSION/Nutrition in the Diabetic Hypertensive

nephropathy. These targets are irrespective of age

(although data concerning patients over the age of

85 years are lacking) and imply an aggressive treat-

ment for isolated systolic hypertension. Attention

should also be given to other modifiable cardiovascu-

lar risk factors (currently smoking and hypercholes-

terolemia; high-density lipoprotein cholesterol may

be included in the future).

Renal Hypertension

0008 This form of hypertension is associated with diabetic

nephropathy. Diabetic renal damage develops in up to

40% of type 1 diabetics and is associated with high

morbidity and mortality. Raised blood pressure may

be present at the clinical onset of renal disease (per-

sistent proteinuria), or emerge during the develop-

ment of nephropathy, when the glomerular filtration

rate begins to decline. There is good evidence that the

presence of hypertension at this stage accelerates the

progression to renal failure. Hence, hypertension may

develop secondarily to renal involvement in diabetes

and, once manifest, accelerates the decline in renal

function. The pathogenesis of hypertension in dia-

betic patients with overt nephropathy is unclear.

However, a predisposition to hypertension and ische-

mic heart disease (positive family history) increases

the susceptibility of type I diabetics to renal disease.

This is thought to imply the involvement of genetic

factors but these have yet to be identified.

Dietary Management of Hypertension in

the Diabetic

0009 Drug treatment of established hypertension is inevit-

ably lifelong. Side-effects of antihypertensive agents

are common and metabolic sequelae could theoretic-

ally contribute to cardiovascular risk (for example, by

increasing insulin resistance). In addition, overzeal-

ous lowering of blood pressure with drugs may have

deleterious effects, especially in the elderly and

in subjects with cardiac disease. The above consider-

ations emphasize that nonpharmacological appro-

aches should be recommended for all subjects with

mild hypertension and dietary manipulation is the

most important of these.

Weight Reduction

0010 Weight loss is the first-line therapy for obese hyper-

tensive diabetic subjects, since this may have a bene-

ficial effect on both blood pressure and blood glucose

control. Weight reduction was shown to lower blood

pressure in the Hypertension Control Program study

where 39% of patients who had previously required

drug therapy for hypertension were controlled by

dietary manipulation alone after 4 years. However,

the effect of weight loss on blood pressure can be

disappointing: a study of 60 mildly hypertensive

obese individuals concluded that weight loss was

not important in lowering blood pressure. Despite

these reservations, weight reduction remains a sens-

ible aim since achievement of a desirable weight for

height, as indicated by the body mass index, may

normalize glucose tolerance in a proportion of pa-

tients with type 2 diabetes as well as reducing insulin

resistance.

0011Dietary recall histories are often used to assess the

energy intake of a patient and a deduction of 500 kcal

from this figure then determines the recommended

energy intake to achieve weight loss of 1–2 kg per

month. Unfortunately, this method consistently

underestimates daily energy intake (by as much as

800 kcal) and, by setting impossible goals for pa-

tients, may lead to poor dietary compliance. It is

possible to calculate the energy intake of a weight-

stable individual using a nomogram in which age, sex,

exercise status, and body mass are taken into account.

A realistic weight-reducing diet aims for an energy

deficit of not more than 500 kcal from the intake

calculated by this method.

0012When placed on a low-energy diet in a controlled

environment all obese subjects lose weight. In the

clinical setting and despite realistic dietary targets, a

substantial proportion of patients do not achieve

weight reduction. Even those who lose weight in the

short term often have difficulty in maintaining this

desirable state. In both cases, this presumably reflects

poor compliance with dietary advice. Second-line

therapy, such as behavioral therapy, may then be

tried as an adjunct to continued attempts at low

energy intake. Behavior therapy is aimed at the iden-

tification and avoidance of cues that promote eating.

Excellent results can be achieved but at great cost in

time to both therapist and patient. In those grossly

overweight subjects who are unable to muster the

self-discipline to lose more than a few kilograms,

surgical procedures may be indicated. Drug therapies

have now largely been withdrawn due to their poor

side-effect profiles.

The ‘Prudent Diet’

0013Irrespective of the need to lose weight, the nutritional

considerations for treating individuals with diabetes

mellitus and hypertension are to improve glycemic

control, lower blood pressure, and reduce hyperlipid-

emia. The composition of the most commonly pre-

scribed dietary regimen is high in dietary fiber

(40–45 g 24 h

1

) with more than 50% of total energy

as unrefined carbohydrate. Dietary fat intake is re-

duced to less than 25% of total energy, with less than

10% in the form of saturated fat. This is known as the

HYPERTENSION/Nutrition in the Diabetic Hypertensive 3201

‘prudent diet.’ In a study of 34 diabetic patients with

essential hypertension, modification of dietary regi-

men in this way, without attempts to reduce overall

energy intake, led to a significant fall in blood pres-

sure over 3 months. Patients also lost a mean of 2 kg

in weight, possibly due to the dietary fiber promoting

satiety at a lower level of calorie and fat intake.

Longer-term studies (up to 4 years) indicate that the

effect on blood pressure is sustained.

0014 Not all authors agree with this form of dietary

manipulation. Reaven and coworkers claim that the

replacement of fat by complex carbohydrate induces

a rise in serum triglyceride levels. Since hypertrigly-

ceridemia is a common abnormality in type 2 dia-

betes, it is argued that the prescribed diet should not

aggravate this situation. It is claimed that replace-

ment of saturated fat with polyunsaturates, without

altering the relative proportions of energy derived

from fat and carbohydrate, alleviates this problem

whilst retaining beneficial effects on glycemic control

and serum cholesterol levels. This alternative dietary

manipulation is given further support by reports that

even dietary enthusiasts find it very difficult to main-

tain the high fiber and carbohydrate intake of the

‘prudent diet.’

Sodium Intake

0015 Sodium intake is also linked with high blood pres-

sure. Double-blind cross-over studies have shown

that moderate sodium restriction (not adding salt,

avoiding salt-laden foods) produces a beneficial effect

on blood pressure. Diabetics appear to be especially

sensitive to salt reduction and this may be related to

the findings of impaired sodium excretion and a 10%

increase in total body exchangeable sodium in diabet-

ics. However, a study of obese patients treated by

weight reduction found no difference in blood pres-

sure in those subjects who did not alter their salt

intake compared with those who restricted salt.

0016 In the UK, the majority of salt intake comes from

the preparation of processed foods and patients may

have a large impact on salt intake by adopting a

diet rich in fruit and vegetables, thereby reducing

consumption of heavily salted products. In this set-

ting, it may be counterproductive to advise further

salt restriction and run the risk of diminished dietary

compliance. An exception to this is the African-

Caribbean diet which is often salt-rich; in this setting

the use of other herbs and spices might effect a sig-

nificant reduction in sodium intake.

Alcohol

0017 Epidemiological studies have convincingly estab-

lished a link between regular alcohol consumption

and high prevalence of hypertension. In individual

subjects regular alcohol intake has been shown to

raise blood pressure and reduction of alcohol con-

sumption is therefore recommended to reduce blood

pressure, as well as to promote weight loss by redu-

cing calorific intake.

Other Dietary Manipulations

0018There are published studies of other dietary manipu-

lations that have been shown to be of benefit in

lowering blood pressure. Calcium supplementation

lowers diastolic blood pressure in young people with

mild hypertension and potassium supplementation

has been shown to reduce blood pressure. Magnesium

supplements may also benefit hypertensive patients

on long-term diuretics. In untreated subjects, chang-

ing to a vegetarian diet may bring about a worthwhile

fall in systolic blood pressure. Until further evidence

is forthcoming, it is premature to advise supplemen-

tation with these minerals; in addition, there is clearly

a limited amount of dietary advice with which pa-

tients can comply.

Recommendations

0019At present, most physicians in the UK would advise

the following measures as the mainstay of dietary

therapy:

0020weight reduction, so as to achieve a stable body

mass index of less than 27 kg m

2

. 0021moderate alcohol restriction (less than two units of

alcohol per day with one alcohol-free day per week)

0022moderate salt restriction (no more than 3 g day

1

)

0023These maneuvers may delay or limit the use of

drugs and in some patients will achieve adequate

blood pressure control. In subjects with mild hyper-

tension, nonpharmacological treatment alone should

be tried for at least 3 months. If the patient is making

good progress, for example with regard to weight

loss, these measures may be pursued for longer. If

the improvement has been small then drug therapy

is appropriate at this stage. In subjects with severe

hypertension drug therapy may be commenced

immediately, since nonpharmacological treatment

alone is unlikely to be effective.

Special Considerations – Diabetic Nephropathy

0024In type 1 diabetics with established renal disease,

there is evidence that protein restriction (to less

than 40 g day

1

), in addition to the dietary measures

outlined above, will retard the progressive decline

in renal function. At this stage, however, hyper-

tension should always be treated with drug

therapy as well. Indeed, many would argue for the

3202 HYPERTENSION/Nutrition in the Diabetic Hypertensive

angiotensin-converting enzyme inhibitor class of anti-

hypertensive drugs to be introduced as a protective

measure before hypertension is established.

Prognosis

0025 Hypertension contributes to the leading causes of

morbidity and mortality in the diabetic population,

namely coronary heart disease, stroke, peripheral vas-

cular disease, lower-extremity amputations, and end-

stage renal disease. Raised blood pressure will also

worsen diabetic retinopathy, a major cause of blind-

ness in the western world. Clearly, the aim of therapy

is to reduce the incidence of these sequelae, especially

premature cardiovascular disease, which is quantita-

tively the most important.

0026 The effectiveness of antihypertensive drug therapy

in reducing elevated blood pressure levels is well

established. In addition, major multicenter trials

of antihypertensive drug therapy have consistently

demonstrated a reduction in the rate of strokes by

approximately one-third and a decrease in cardiovas-

cular mortality by around 15%. Large long-term

studies of antihypertensive therapy have now been

performed in diabetic populations and have con-

firmed that this group of patients benefits from

aggressive control of hypertension and other cardio-

vascular risk factors. Indeed, there are many guide-

lines suggesting that type 1 diabetics with incipient

nephropathy (microalbuminuria at high risk of de-

veloping overt diabetic nephropathy) should receive

antihypertensive drug therapy whilst their blood pres-

sure is still within the normal range.

Prevention

0027 Until the etiology of essential hypertension and dia-

betic nephropathy is more fully understood, preven-

tion will remain difficult. As yet, there is no evidence

that strict control of blood glucose can prevent the

development of either condition, although once pre-

sent, hyperglycemia may increase proteinuria. This

is in keeping with evidence that both essential

hypertension and diabetic renal disease have strong

genetic components. Nevertheless, it is sensible to

advise all diabetics to take a diet low in saturated

fat, to moderate their salt intake, and avoid excessive

alcohol consumption. Regular exercise is recom-

mended and obesity should be avoided. These

measures may delay, or even prevent, the onset of

hypertension in type 2 diabetics but are unlikely to

affect the development of hypertension in association

with diabetic nephropathy.

0028Finally, since the main aim of treating high blood

pressure is to effect a reduction in the number of

cardiovascular events, it is appropriate to focus atten-

tion on other cardiovascular risk factors such as

smoking and hypercholesterolemia. These also have

important dietary aspects; stopping smoking is often

associated with weight gain; treatment of hypercho-

lesterolemia is through dietary manipulation, at least

in the first instance.

See also: Alcohol: Properties and Determination;

Metabolism, Beneficial Effects, and Toxicology; Diabetes

Mellitus: Etiology; Chemical Pathology; Treatment and

Management; Problems in Treatment; Secondary

Complications; Obesity: Etiology and Diagnosis; Renal

Function and Disorders: Nutritional Management of

Renal Disorders; Slimming: Slimming Diets; Sodium:

Properties and Determination; Physiology

Further Reading

Bain SC and Dodson PM (1991) Managing the obese pa-

tient with hypertension. Treating Overweight 21: 2–6.

Barnett AH and Dodson PM (eds) (1990) Hypertension and

Diabetes. London: Science Press.

Bursztyn P (1987) Nutrition and Blood Pressure. South-

ampton, UK: John Libbey.

Collins R, Peto R, MacMahon S et al. (1990) Blood pres-

sure, stroke and coronary heart disease. Part 2, short

term reductions in blood pressure: overview of random-

ised drug trials in their epidemiological context. Lancet

i: 827–838.

Lean MEJ and James WPT (1986) Prescription of diabetic

diets in the 1980s. Lancet i: 723–725.

Reaven GM (1988) Role of insulin resistance in human

disease. Banting lecture. Diabetes 37: 1595–1607.

Reaven GM (1988) Dietary therapy for non-insulin-

dependent diabetes mellitus. New England Journal of

Medicine 319(13): 862–864.

Stamler R, Stamler J, Grimm R et al. (1987) Nutritional

therapy for high blood pressure. Final report of a four-

year randomised controlled trial – the hypertension con-

trol program. Journal of the American Medical Associ-

ation 257(11): 1484–1491.

Swales JD, Ramsey LE, Coope JR et al. (1989) Report of

the British Hypertension Society working party. Treating

mild hypertension. British Medical Journal 298:

694–698.

HYPERTENSION/Nutrition in the Diabetic Hypertensive 3203

HYPOGLYCEMIA (HYPOGLYCAEMIA)

M S Boyne, University of the West Indies, Mona,

Jamaica

Background

0001 Hypoglycemia was not clinically appreciated until

the discovery of insulin by Banting, Best, Collip, and

MacLeod. In 1921, they noted that unpurified insulin

led to the sudden death of several test animals. Subse-

quently, patients with type 1 diabetes treated with

insulin described the symptoms now attributed to

hypoglycemia. It was soon observed that some non-

diabetic patients demonstrated similar symptoms,

and the concept of spontaneous hypoglycemia or

‘hyperinsulinism’ was promoted. The cause remained

unclear until 1927, when Wilder et al. described a

surgeon with a malignant pancreatic tumor that had

insulin-like biological activity (i.e., an insulinoma).

Hyperinsulinism was also described in children of

diabetic mothers in the 1920s and was ascribed

to ‘compensatory hypertrophy of the pancreas.’ By

1933, it was recognized that hypoglycemia was

caused by several conditions, including adrenal insuf-

ficiency, starvation, cirrhosis, and critical illness.

0033 In 1938, Whipple described the triad of criteria

necessary for the diagnosis of hypoglycemia, i.e.,

symptoms consistent with hypoglycemia, blood glu-

cose concentration less than 2.8 mmol l

1

and imme-

diate relief by the ingestion of glucose. The ability to

measure plasma insulin by radioimmunoassay in

1959 confirmed that not all hypoglycemia was due

to hyperinsulinism. Also, the elucidation of the bio-

chemical pathways of glucose, amino acid, and lipid

metabolism has led to the recognition of a plethora of

congenital causes of hypoglycemia. Consequently, in

this chapter, the regulatory mechanisms of glucose

homeostasis are first described to provide the basis

for understanding the pathophysiology of hypo-

glycemia. The common causes of hypoglycemia are

then outlined.

Definition

0002 The Third International Symposium on Hypogly-

cemia in 1986 defined hypoglycemia as a blood

glucose concentration less than 2.8 mmol l

1

, thus

endorsing Whipple’s criteria. Many clinicians,

while suspicious of hypoglycemia at this threshold,

do not diagnose hypoglycemia until levels are

below 2.2 mmol l

1

. However, others argue that

hypoglycemia could be defined at higher levels, as

physiological responses to lowering of blood glucose

begin at 4.0–4.2 mmol l

1

with the suppression of

endogenous insulin secretion.

Physiological Defenses against

Hypoglycemia

0003Plasma glucose in humans is maintained within the

relatively narrow range of 3.6–7.8 mmol l

1

, whether

in the fasting (postabsorptive) or fed (postprandial)

state. This is accomplished by the tight regulation and

coupling of glucose utilization and production, each

*10–14 mmol glucose kg

1

min

1

. The incidence of

hyperglycemia is vastly greater than hypoglycemia,

as the body has developed several mechanisms to

combat life-threatening hypoglycemia. This mainten-

ance of glucose balance is necessary, since the brain

has a critical dependence for glucose as an energy

source. Other organs such as muscle, liver, heart,

kidney, and adipose tissue can utilize other metabolic

substrates to provide the energy necessary for main-

tenance and growth. The brain, however, has a re-

spiratory quotient of 0.97–0.99 under physiological

conditions, indicating its almost exclusive use of glu-

cose. Despite this dependency, the brain has no en-

zymatic machinery for significant glycogen synthesis

or gluconeogenesis. Consequently, it depends upon a

continuous, high concentration of glucose in the

arterial blood. In fasting conditions, the arterial

concentration of glucose becomes limiting, the

blood-to-brain glucose transport mediated by glucose

transporters (GLUT-1 and 3) decreases, and neuronal

function is impaired. The brain can subsist on ketone

bodies (i.e., acetoacetate, b-hydroxybutyrate), if their

plasma concentration rises to the threshold necessary

to pass the blood–brain barrier, but this only occurs

during prolonged fasting.

0004During hypoglycemia, counter-regulatory mechan-

isms convert the liver into an organ of net glucose

export, provide alternative metabolic fuels, and de-

crease glucose utilization. During fasting (i.e., > 6 h

after a meal), the liver maintains physiological

concentrations of plasma glucose by glycogenolysis

and gluconeogenesis. Initially, glycogenolysis takes

precedence, accounting for 70–90% of the total glu-

cose production. However, in the absence of gluco-

neogenesis, the liver’s glycogen stores of 40–90 g are

depleted in 8–10 h. Subsequently, hepatic gluconeo-

genesis becomes the prime source of glucose produc-

tion. Renal gluconeogenesis only becomes important

3204 HYPOGLYCEMIA (HYPOGLYCAEMIA)

during prolonged fasting when it may contribute up

to half of the total glucose production. Proteolysis

provides the main gluconeogenic precursors (alanine,

lactate) catabolized from the carbon skeletons of

amino acids via the Cori and lactate cycles.

0005 The rate of lipolysis increases, providing nonester-

ified free fatty acids for conversion to ketone bodies

by the liver. Muscle and fat can efficiently utilize fatty

acids and ketones for fuel, so glucose utilization by

these tissues almost ceases. After several days of

fasting, the plasma concentration of ketone bodies

rises to the level that supports transfer across the

blood–brain barrier. Ketone bodies then become a

source of energy for the brain, decreasing its need

for glucose by approximately 50%. Thereafter, gluco-

neogenesis decreases, resulting in a protein-sparing

effect. The rate of total glucose utilization eventually

nadirs at *5 mmol kg

1

min

1

, and correspondingly,

plasma glucose levels fall to a plateau of 2.5–

3.3 mmol l

1

. These levels can be maintained for

several weeks.

Hormonal Mechanisms

0006 The above catabolic pathways are under hormonal

regulation. When plasma glucose falls, intracellular

signals in b-cells, possibly including glucokinase as

a glucose sensor, lead to inhibition of insulin secre-

tion (Figure 1). Consequently, glucose uptake by

peripheral tissues, especially muscle, and glycogen

synthesis in muscle and liver (via decreased glycogen

synthetase activity and increased phosphorylase

activity) is halted. Gluconeogenesis is stimulated as

phosphoenolpyruvate carboxykinase and fructose-

1,6-bisphosphatase activity is increased. Also, insu-

lin’s inhibition of hormone-sensitive lipase is released,

leading to lipolysis (Figure 2). However, the suppres-

sion of insulin secretion is not the predominant factor

in the correction of hypoglycemia. This is seen in the

spontaneous recovery from acute insulin-induced

hypoglycemia prior to the dissipation of insulin.

Hence, other counter-regulatory factors must be in-

volved to overcome the effects of the relative hyper-

insulinemia.

0007Using the hyperinsulinemic stepped hypoglyce-

mic clamp technique, it was shown that glucose

levels 3.7 mmol l

1

stimulate the secretion of the

counter-regulatory hormones glucagon, epinephrine,

growth hormone, and cortisol. Glucagon and epi-

nephrine serve as the major glucose-raising hor-

mones. Glucagon acts directly and rapidly on the

liver, augmenting glycogenolysis (by increasing glyco-

gen phosphorylase activity) and gluconeogenesis (via

fructose-1,6-bisphosphatase activity). It has no extra-

hepatic effect on glucose uptake, and its effects are

potent, accounting for approximately 40% of glucose

recovery. However, they are transient, as its plasma

half-life is only 5–10 min before hepatic degradation

occurs.

0008Epinephrine, acting through plasma membrane

adrenergic receptors, stimulates glucagon release, in-

hibits insulin secretion, promotes lipolysis and prote-

olysis thereby mobilizing gluconeogenic precursors,

and decreases peripheral glucose utilization. Epine-

phrine’s effects become extremely critical if glucagon

is deficient. Growth hormone and cortisol contribute

+ β

− α

β cell

α cell

Insulin

Glucagon

Hypoglycemia

Growth

hormone

Cortisol Epinephrine

Adrenal

gland

Via

sympathetic

outflow

ACTH

Pituitary

gland

fig0001 Figure 1 Effect of hypoglycemia on hormonal secretion. a

and b

, receptor-mediated effects of epinephrine.

HYPOGLYCEMIA (HYPOGLYCAEMIA) 3205

if hypoglycemia persists for several hours and is

severe. They act by antagonizing insulin effects,

inducing a slower recovery from hypoglycemia.

Thresholds for Symptoms of

Hypoglycemia

0009 The fall of blood glucose initiates physiological re-

sponses prior to the development of any clinical

symptoms (Figure 3). A plasma glucose level

< 4.2 mmol l

1

suppresses insulin secretion. Counter-

regulatory hormone secretion begins at *3.7

mmol l

1

when sequential signals within the a-cells

promote glucagon secretion. Autonomic nervous

system (ANS) discharge is also increased, which aug-

ments the glucagon response and initiates the epi-

nephrine response. Infusion of glucose into carotid

and vertebral arteries in animal models reduces the

epinephrine response by as much as 75%, and the

ventromedial hypothalamus is one possible anatomic

locus of the ANS signal.

0010 Symptoms are not experienced until the blood glu-

cose levels fall below 3.1 mmol l

1

. These symptoms

are classified as neurogenic or neuroglycopenic. The

former includes symptoms induced by the activation

of the sympathetic (adrenergic) system and the vagal

(cholinergic) system. They include sweating, tremor,

anxiety, palpitations, pallor, tingling, and hunger. The

neuroglycopenic symptoms occur when the blood

glucose levels fall to * 2.6 mmol l

1

, although there

is individual variation. They include poor concentra-

tion, inattention, confusion, blurred vision, dizziness,

weakness, and fatigue. If the blood glucose falls fur-

ther, more severe cognitive disturbances develop such

as behavioral changes, stupor, seizure, coma, and

death.

Classification of Hypoglycemic Disorders

0011Traditionally, hypoglycemia is classified as either

fasting or postprandial (Tables 1 and 2), but it can

also be classified on the basis of insulin mediation,

state of heath, or age of the patient. Irrespective of the

method of classification, most cases of hypoglycemia

are attributable to hyperinsulinemic hypoglycemia in

individuals with diabetes mellitus from subcutaneous

insulin injections, or oral sulfonylureas. (See Diabetes

Mellitus: Problems in Treatment.) It should be noted

that in the evaluation of hypoglycemia, artifactual

causes i.e., improper sample collection or storage

resulting in hemolysis, increased utilization of glucose

after phlebotomy by the large number of leucocytes in

certain leukemias, and errors in laboratory analysis,

need to be excluded.

Postprandial or Food-stimulated

Hypoglycemia

0012Postprandial hypoglycemia is hypoglycemia occur-

ring 2–5 h after a meal. It is a self-limiting condition

with no associated mortality, although its morbidity

may have been underestimated. It has been described

as an epidemic affecting the USA and Europe as more

people are presenting self-diagnosed. The majority of

Release

of inhibition

of hormone

sensitive

lipase

?β

NEFA

Glycerol

Lipolysis Glycogenolysis

Gluconeogenesis

Proteolysis

Glycogenolysis

Glycolysis

Cortisol

EpinephrineGlucagon

Insulin

Alanine

Lactate

fig0002 Figure 2 (see color plate 96) Hormonal effects on glucose metabolism during fasting. b

, b

and b

, receptor-mediated effects of

epinephrine; NEFA, nonesterified fatty acids.

3206 HYPOGLYCEMIA (HYPOGLYCAEMIA)

patients, however, do not fulfill the requirements of

Whipple’s triad. Misdiagnosis also occurs due to

the over-reliance on oral glucose tolerance testing

(OGTT) and/or capillary (‘finger-stick’) glucose for

diagnosis. Home reflectance meters for measuring

capillary glucose are notoriously unreliable in the

hypoglycemic range.

0013 A common cause of postprandial hypoglycemia is

alimentary hypoglycemia. This generally occurs in

individuals who have had gastrointestinal surgery,

e.g., gastric bypass, pyloroplasty, and gastrectomy,

although a few have normal gastrointestinal tracts.

The reported prevalence in postsurgical patients

varies between 5 and 37%. The postulated mechan-

ism is rapid transition of ingested food into the upper

small intestine, leading to early, severe hyperglycemia

(frequently 14 mmol l

1

). This induces the release

of local gut factors (incretins), such as glucagon-like

peptide-1 and glucose-dependent insulin-releasing

peptide, resulting in insulin hypersecretion and glu-

cose levels falling to < 2.8 mmol l

1

within 2–3h.

Dumping syndrome has to be considered in this

setting as it has similar symptoms, but these occur

within an hour after meals due to transluminal os-

motic/fluid shifts. Treatment of alimentary hypogly-

cemia involves frequent feedings of high-fiber meals

or low-carbohydrate/high-protein meals. Pectin, fruc-

tose, uncooked cornstarch, chromium, medium-chain

triacylglycerol, octreotide, propanolol, sulfonylureas,

tbl0002Table 2 Causes of fasting hypoglycemia

Medications

Alcohol

Protein–energy malnutrition

Severe medical illness

Liver failure

Renal failure

Cardiac failure

Sepsis

Endocrinopathies

Adrenal insufficiency

Growth hormone deficiency

Isolated glucagon or epinephrine deficiency

Insulinoma (endogenous hyperinsulinemia)

Isolated

Part of multiple endocrine neoplasia-1 syndrome

Noninsulinoma pancreatogenous hypoglycemia

Noninsulinoma tumor-associated hypoglycemia

Factitious hypoglycemia

Malingering

Psychiatric disorders including Munchausen’s syndrome

Pharmacy error

Autoimmune antiinsulin antibody syndrome

Ackee poisoning (Jamaican vomiting sickness)

tbl0001 Table 1 Causes of postprandial hypoglycemia

Alimentary hypoglycemia

Secondary to previous gastrointestinal surgery, especially for

peptic ulcer disease and gastrointestinal motility syndromes

Idiopathic postprandial hypoglycemia

Congenital deficiencies of enzymes of carbohydrate metabolism

Hereditary fructose intolerance

Galactosemia

Defective hepatic gluconeogenesis,

e.g., fructose-1,6-bisphosphatase deficiency

Gin-and-tonic hypoglycemia

Leucine insensitivity

Causes of fasting hypoglycemia, especially insulinoma

1.0

2.0

3.0

Plasma glucose concentration (mmoll

−1

)

Insulin (4.2)

Glucagon (3.6), epinephrine

Cortisol, GH (3.3)

Neurogenic symptoms (3.0), mild cognitive defects

Neuroglycogenic symptoms (2.5)

Stupor (1.6)

Seizure, coma, death (1.1)

4.0

fig0003 Figure 3 Glycemic thresholds during progressive hypoglycemia.

HYPOGLYCEMIA (HYPOGLYCAEMIA) 3207

a-glucosidase inhibitors, metformin, and doxepin

have also been proposed as alternatives, but none

of these therapies have been properly evaluated in

controlled trials.

0014 It is controversial whether there really is an entity

of idiopathic postprandial hypoglycemia. Most have

been diagnosed on the grounds of diffuse symptoms

and biochemical hypoglycemia by OGTT. In a

study of 650 normal subjects, 10% had nadir values

of < 2.6 mmol l

1

, and 2.5% were < 2.16 mmol l

1

during a 100-g OGTT. Consequently, it would seem

unwise to use an arbitrary diagnostic cut-off, since

none of these patients had any significant symptoms

or long-term adverse effects. In fact, 4.8% of normal

individuals have blood glucose values 3.0 mmol l

1

in free-living situations. When a group of 118 patients

with suspected hypoglycemia were studied, only

16 had confirmed hypoglycemia (the mean was

2.2 mmol l

1

) during symptoms. The other 102 pa-

tients were symptomatic, but there was no relation-

ship to blood glucose levels or meals, and their nadirs

were similar to those of the control group. Fourteen

of these patients also had placebo-OGTT tests, which

provoked characteristic symptoms. Another group of

investigators confirmed the invalidity of OGTT and

also hypothesized that mixed meal tolerance tests of

550 and 825 kcal should provide a more physio-

logical stimulus to provoke symptoms. The meals

did not induce biochemical hypoglycemia, but the

patients had characteristic symptoms. In another

study, there was a poor correlation between the oc-

currence of symptoms and plasma glucose concentra-

tions in ambulatory patients. Any abnormalities were

not reproducible.

0015 Based on these studies and others, it is generally

agreed that an OGTT should not be used in the evalu-

ation of idiopathic postprandial hypoglycemia, as its

predictive power is poor (positive predictive value

21–31%, negative predictive value 68–100%). In-

stead, documenting hypoglycemia after meals that

historically provoke hypoglycemia is more useful. It

has been suggested that symptomatic individuals

without biochemical hypoglycemia should be given

the diagnosis of idiopathic postprandial syndrome

or pseudohypoglycemia, since factors other than

hypoglycemia are operative, while giving validity to

their symptomatology. Other potential mechanisms,

such as the rate of glucose decline, excessive insulin

secretion, and plasma cortisol responses have not

been proven to be significant. Increased tissue sensi-

tivity to insulin may play a role in some individuals.

Glucagon responses have not been consistent

between studies, but may be subnormal. Exaggerated

plasma epinephrine responses have been reported in

uncontrolled studies. In any event, other investigators

have shown that epinephrine and cortisol concentra-

tions do not increase during the symptoms, indicating

that no significant autonomic activation is present. It

should be noted that over 50% of patients with idio-

pathic postprandial syndrome also have evidence of

conversion reactions with high scores on the depres-

sion, hysteria, and hypochondriasis scales on psycho-

logical testing. In one study, 45% had somatoform

disorders, 35% had depressive affective disorders,

20% had no evidence of a psychiatric disorder, and

only 3% had true idiopathic postprandial hypogly-

cemia. Hence, idiopathic postprandial hypoglycemia

is a rare entity, unlike the more common idiopathic

postprandial syndrome. Treatment involves dietary

restriction of refined carbohydrates and avoiding

caffeine and alcohol.

0016Other conditions causing postprandial hypogly-

cemia include galactosemia and hereditary fructose

intolerance that usually present during childhood.

Rarely, leucine intake can cause hypoglycemia in

susceptible individuals. As early as 1924, it was sug-

gested that postprandial hypoglycemia occurs in

the early phase of type 2 diabetes mellitus. However,

this work was based on OGTTs, and only *5% of

patients were symptomatic. It was postulated that

abnormal b-cell responses to glucose loads lead to

hyperinsulinemia. Individuals with fasting hypogly-

cemia, especially insulinomas, may also have post-

prandial hypoglycemia. A high intake of alcohol

with simple carbohydrates and no complex carbohy-

drates (such as gin and tonic) can lead to symptomatic

hypoglycemia within 3–4 h in 10–20% of normal

individuals. It is thought that the hypoglycemia is

due to an insulinotrophic effect of ethanol in response

to sucrose.

Fasting Hypoglycemia

0017The causes of fasting hypoglycemia are numerous and

are outlined in Table 2. In many cases, the cause is

evident, such as in an ill patient with multiorgan

failure, but in others, especially ambulatory patients,

it may not be obvious. In these individuals, it is neces-

sary to measure simultaneously plasma glucose,

insulin, C-peptide, and sulfonylurea levels during

the episode of hypoglycemia. If insulin levels are not

available, serum or urine ketone levels can give an

indication of insulin mediation, as ketone levels are

raised in hypoinsulinemic states.

Drugs

0018Drugs are a frequent cause of hypoglycemia, and

some of the more common drugs are listed in Table 3

along with their putative mechanism. Other drugs

have been alleged to cause hypoglycemia, but a causal

3208 HYPOGLYCEMIA (HYPOGLYCAEMIA)