12 Carbohydrate metabolism - PowerPoint Presentation

Slide1

12

Carbohydrate metabolism

Chemistry

176

Hyperglycaemia and diabetes mellitus

183

Physiology

176

Hypoglycaemia

194

This chapter discusses carbohydrate metabolism and its

synthesize glucose,

abnormalities, with emphasis on diabetes mellitus and

store glucose in significant amounts,

hypoglycaemia. In the next decade it is predicted that

metabolize substrates other than glucose and ketones

there will be about 250 million people worldwide with

- plasma ketone concentrations are usually very low

type 2 diabetes mellitus.

and ketones are of little importance as an energy

source under physiological conditions,

CHEMISTRY

extract enough glucose from the extracellular fluid

The main monosaccharide hexoses are reducing sugars.

(ECF) at low concentrations for its metabolic needs,

Naturally occurring polysaccharides are long-chain

because entry into brain cells is not facilitated by

carbohydrates composed of glucose subunits (Table

insulin.

12.1):

Normally the plasma glucose concentration remains

Starch , found in plants, is a mixture of amylose

between about 4 mmol/L and 10 mmol/L, despite the

(straight chains) and amylopectin (branched

intermittent load entering the body from the diet. The

chains).

maintenance of plasma glucose concentrations below

Glycogen , found in animal tissue, is a highly branched

about 10 mmol/L minimizes loss from the body as well

polysaccharide.

as providing the optimal supply to the tissues. Renal

tubular cells reabsorb almost all the glucose ?ltered

PHYSIOLOGY

by the glomeruli, and urinary glucose concentration

Functions of extracellular glucose

is normally too low to be detected by the usual tests,

The main function of glucose is as a major tissue energy

Glucose

source. The simplified pathways of glycolysis and the

Krebs cycle [tricarboxylic acid (TCA) cycle] are shown

Hexose phosphates

in Figures 12.1 and 12.2. The brain is highly dependent

upon the extracellular glucose concentration for its

energy supply; indeed, hypoglycaemia is likely to impair

Triose phosphates

cerebral function or even lead to irreversible neuronal

damage. This is because the brain cannot:

2-Phosphoglycerate

Table 12.1 Common reducing and non-reducing sugars

Phosphoenolpyruvate

Reducing sugars

Non-reducing sugars

Monosaccharides

Glucose

Pyruvate

Fructose

Galactose

Lactate

Disaccharides

Lactose

Sucrose

Figure 12.1 Simpli?cation of glycolysis pathways.

(galactose + glucose)

(fructose + glucose)

Reproduced with kind permission from Candlish

Maltose

JK and Crook M. Notes on Clinical Biochemistry .

(glucose + glucose)

Singapore: World Scienti?c Publishing, 1993.

Physiology

177

Insulin

Glucose-

Ribose-

Glucose

6-phosphate

5-phosphate

Insulin is the most important hormone controlling

plasma glucose concentrations. A plasma glucose

TPP

Transketolase

concentration of greater than about 5 mmol/L acting via

the glucose transporter 2 stimulates insulin release from

Sedoheptulose-

Fructose-

7-phosphate

the pancreas b -cell. These cells produce proinsulin, which

6-phosphate

consists of the 51-amino-acid polypeptide insulin and a

linking peptide (C-peptide, Fig. 12.3). Splitting of the

peptide bonds by prohormone convertases releases via

Fructose-1,

intermediates (mostly 32-33 split proinsulin) equimolar

6-diphosphate

amounts of insulin and C-peptide into the ECF.

Insulin binds to speci?c cell surface receptors on

muscle and adipose tissue, thus enhancing the rate

Pyruvate

Lactate

of glucose entry into these cells. Insulin-induced

Pyruvate

activation of enzymes stimulates glucose incorporation

TPP

dehydrogenase

into glycogen (glycogenesis) in liver and muscle (Fig

12.4). Insulin also inhibits the production of glucose

Acetyl CoA

(gluconeogenesis) from fats and amino acids, partly

by inhibiting fat and protein breakdown (lipolysis and

Oxaloacetate

Citrate

proteolysis).

The transport of glucose into liver cells is insulin

independent but, by reducing the intracellular glucose

concentration, insulin does indirectly promote the

a -Ketoglutarate

Succinate

passive diffusion of glucose into them. Insulin also

a -Ketoglutarate

directly increases the transport of amino acids,

dehydrogenase

TPP

potassium and phosphate into cells, especially muscle;

these processes are independent of glucose transport.

Figure 12.2 Simpli?cation of the tricarboxylic acid (Krebs)

cycle. CoA, coenzyme A; TPP, thiamine pyrophosphate.

In the longer term, insulin regulates growth and

Reproduced with kind permission from Candlish JK and

development and the expression of certain genes.

Crook M. Notes on Clinical Biochemistry . Singapore:

Glucagon

World Scienti?c Publishing, 1993.

Glucagon is a single-chain polypeptide synthesized

by the a -cells of the pancreatic islets. Its secretion is

even after a carbohydrate meal. Signi?cant glycosuria

stimulated by hypoglycaemia. Glucagon enhances

usually occurs only if the plasma glucose concentration

hepatic glycogenolysis (glycogen breakdown) and

exceeds about 10 mmol/L - the renal threshold.

gluconeogenesis.

How the body maintains extracellular

glucose concentrations

Control of plasma glucose concentration

C-PEPTIDE

During normal metabolism, little glucose is lost

unchanged from the body. Maintenance of plasma

COO -

glucose concentrations within the relatively narrow

NH 3+

range of 4-10 mmol/L, despite the widely varying input

S

S

from the diet, depends on the balance between the

S

S

glucose entering cells from the ECF and that leaving

S

INSULIN

them into this compartment.

S

Hormones concerned with glucose homeostasis

Figure 12.3 Structure of proinsulin, indicating the

Some of the more important effects of hormones on

cleavage sites at which insulin and C-peptide are

glucose homeostasis are summarized in Table 12.2.

produced.

Carbohydrate metabolism

178

Table 12.2 Action of hormones that affect intermediary metabolism

Insulin

Glucagon

Growth hormone

Glucocorticoids

Adrenaline

Carbohydrate metabolism

In liver

Glycolysis

+

Glycogenesis

+

Glycogenolysis

+

+

Gluconeogenesis

-

+

+

In muscle

Glucose uptake

+

-

-

Glycogenesis

+

Glycogenolysis

+

Protein metabolism

Synthesis

+

+

Breakdown

-

+

Lipid metabolism

Synthesis

+

Lipolysis

-

+

+

+

Secretion

Stimulated by

Hyperglycaemia

Hypoglycaemia

Hypoglycaemia

Hypoglycaemia

Hypoglycaemia

Amino acids

Amino acids

Stress

Stress

Stress

Glucagon

Fasting

Sleep

Gut hormones

b -blockers

Inhibited by

Adrenaline

Insulin

Somatostatin

Glucocorticoids

Fasting

IGF-1

Somatostatin

Plasma NEFA concentrations

Fall

Rise

Rise

Rise

Rise

Plasma glucose concentrations

Fall

Rise

Rise

Rise

Rise

+, stimulates; -, inhibits; IGF-1, insulin-like growth factor 1; NEFA, non-esteri?ed fatty acid.

Somatostatin

in phaeochromocytoma (adrenaline and noradrenaline

see Chapter 24) and thus oppose the normal action of

This peptide hormone is released from the D cells of

insulin.

the pancreas and inhibits insulin and growth hormone

release.

The liver

Other hormones

The liver is the most important organ maintaining a

When plasma insulin concentrations are low, for

constant glucose supply for other tissues, including the

example during fasting, the hyperglycaemic actions

brain. It is also of importance in controlling the post-

of hormones, such as growth hormone (GH),

prandial plasma glucose concentration.

glucocorticoids, adrenaline (epinephrine) and

Portal venous blood leaving the absorptive area of the

glucagon, become apparent, even if there is no increase

intestinal wall reaches the liver ?rst, and consequently

in secretion rates. Secretion of these so-called counter-

the hepatic cells are in a key position to buffer the

regulatory hormones may increase during stress and

hyperglycaemic effect of a high-carbohydrate meal

in patients with acromegaly (GH, see Chapter 6),

(Fig. 12.5).

Cushing's syndrome (glucocorticoids, see Chapter 8) or

Physiology

179

lactate or the carbon chains resulting from deamination

of certain amino acids (mainly alanine) (Table 12.3). The

liver contains the enzyme glucose-6-phosphatase, which,

by hydrolysing G6P derived from either glycogenolysis

Outer

or gluconeogenesis, releases glucose and helps to

1

1

1

1

branches

1

1

maintain extracellular fasting concentrations. Hepatic

1

glycogenolysis is stimulated by the hormone glucagon,

2

2

1

secreted by the a -cells of the pancreas in response

2

2

to a fall in the plasma glucose concentration, and by

3

catecholamines such as adrenaline or noradrenaline.

3

Inner

branches

During fasting, the liver converts fatty acids,

4

released from adipose tissue as a consequence of low

insulin activity, to ketones. The carbon chains of some

amino acids may also be converted to ketones (Table

12.3). Ketones can be used by other tissues, including

R

the brain, as an energy source when plasma glucose

concentrations are low.

Figure 12.4 Structure of glycogen. Open circles depict

glucose moieties in a -1,4 linkage and the black

Other organs

circles those in a -1,6 linkages at branch points. R

The renal cortex is the only other tissue capable of

indicates the reducing end group. The outer branches

gluconeogenesis, and of converting G6P to glucose. The

terminate in non-reducing end groups. Reproduced

with permission from Nyhan WL and Barshop BA. Atlas

gluconeogenic capacity of the kidney is particularly

of Inherited Metabolic Diseases, 3rd edition. London:

important in hydrogen ion homeostasis and during

Hodder Arnold, 2012.

prolonged fasting.

Other tissues, such as muscle, can store glycogen but,

because they do not contain glucose-6-phosphatase,

The entry of glucose into liver and cerebral cells is

they cannot release glucose from cells and so can only

not directly affected by insulin, but depends on the

use it locally; this glycogen plays no part in maintaining

extracellular glucose concentration. The conversion of

the plasma glucose concentration.

glucose to glucose-6-phosphate (G6P), the ?rst step in

Systemic effects of glucose intake

glucose metabolism in all cells, is catalysed in the liver

by the enzyme glucokinase, which has a low af?nity for

The liver modifies the potential hyperglycaemic effect

glucose compared with that of hexokinase, which is found

of a high-carbohydrate meal by extracting relatively

in most other tissues. Glucokinase activity is induced by

more glucose than in the fasting state from the portal

insulin. Therefore, hepatic cells extract proportionally

plasma. However, some glucose does pass through

less glucose during fasting, when concentrations in

the liver and the rise in the systemic concentration

portal venous plasma are low, than after carbohydrate

ingestion. This helps to maintain a fasting supply of

Table 12.3 Metabolism of the carbon skeleton of some

glucose to vulnerable tissues such as the brain.

amino acids to either carbohydrate (glycogenic) or fat

The liver cells can store some of the excess glucose as

(ketogenic)

glycogen. The rate of glycogen synthesis (glycogenesis)

Glycogenic

Glycogenic and ketogenic

Ketogenic

from G6P may be increased by insulin secreted by

the b -cells of the pancreas in response to systemic

Alanine

Isoleucine

Leucine

hyperglycaemia. The liver can convert some of the excess

Arginine

Lysine

glucose to fatty acids, which are ultimately transported

Glycine

Phenylalanine

as triglyceride in very low-density lipoprotein (VLDL)

Histidine

Tyrosine

and stored in adipose tissue.

Methionine

Under normal aerobic conditions, the liver can

Serine

synthesize glucose by gluconeogenesis using the

Valine

metabolic products from other tissues, such as glycerol,

Carbohydrate metabolism

180

BRAIN

MUSCLE

G6P

Insulin

GLYCOGEN

INTESTINE

CO 2 + H 2 O

G6P

GLUCOSE

Glucose

Insulin

Insulin

G6P

G6P

GLYCOGEN

Triose-P

Triose-P

Acetyl CoA

Fatty acid + Glycerol-3-P

Fatty acid + Glycerol-3-P

Glycerol

Triglyceride

TRIGLYCERIDE

VLDL

LIVER

ADIPOSE TISSUE

Figure 12.5 Post-prandial metabolism of glucose. CoA, coenzyme A; G6P, glucose-6-phosphate; Glycerol-3-P,

glycerol-3-phosphate; Triose-P, triose phosphate or glyceraldehyde 3-phosphate; VLDL, very low-density lipoprotein.

stimulates the b -cells of the pancreas to secrete insulin.

these actions are impaired. Both muscle and adipose

tissue store the excess post-prandial glucose, but the

Insulin may further enhance hepatic and muscle

mode of storage and the function of the two types of

glycogenesis. More importantly, entry of glucose into

cell are very different, as will be shown later.

adipose tissue and muscle cells, unlike that into liver and

brain, is stimulated by insulin and, under physiological

Ketosis

conditions, the plasma glucose concentration falls to

Adipose tissue and the liver

near fasting levels. Conversion of intracellular glucose

Adipose tissue triglyceride is the most important long-

to G6P in adipose and muscle cells is catalysed by the

term energy store in the body. Greatly increased use

enzyme hexokinase, which, because its affinity for

of fat stores, for example during prolonged fasting,

glucose is greater than that of hepatic glucokinase,

is associated with ketosis. Adipose tissue cells, acting

ensures that glucose enters the metabolic pathways in

in conjunction with the liver, convert excess glucose

these tissues at lower extracellular concentrations than

to triglyceride and store it in this form rather than

those in the liver. The relatively high insulin activity

as glycogen. The components are both derived from

after a meal also inhibits the breakdown of triglyceride

glucose, fatty acids from the glucose entering hepatic

(lipolysis) and protein (proteolysis). If there is relative

cells and glycerol from that entering adipose tissue cells.

or absolute insulin deficiency, as in diabetes mellitus,

Physiology

181

In the liver, triglycerides are formed from glycerol-

Most tissues, other than the brain, can oxidize fatty

3-phosphate (from triose phosphate or glyceraldehyde-

acids to acetyl CoA, which can then be used in the TCA

3-phosphate) and fatty acids [from acetyl coenzyme A

cycle as an energy source. When the rate of synthesis

(CoA)]. The triglycerides are transported to adipose

exceeds its use, the hepatic cells produce acetoacetic acid

tissue cells incorporated in VLDL, where they are

by enzymatic condensation of two molecules of acetyl

CoA; acetoacetic acid can be reduced to b -hydroxybutyric

hydrolysed by lipoprotein lipase. The released fatty

acids (of hepatic origin) are re-esteri?ed within these

acid and decarboxylated to acetone. These ketones can

cells with glycerol-3-phosphate, derived from glucose,

be used as an energy source by brain and other tissues at

which has entered this tissue under the in?uence of

a time when glucose is in relatively short supply.

insulin. The resultant triglyceride is stored and is far

Ketosis occurs when fat stores are the main energy

more energy dense than glycogen (see Chapter 13).

source and may result from fasting or from reduced

During fasting, when exogenous glucose is

nutrient absorption, for example due to vomiting. Mild

unavailable and the plasma insulin concentration

ketosis may occur after as little as 12 h of fasting. After

is therefore low, endogenous triglycerides are

short fasts, metabolic acidosis is not usually detectable,

reconverted to free non-esteri?ed fatty acids (NEFAs)

but, after longer periods, more hydrogen ions may

and glycerol by lipolysis (Fig. 12.6). Both are

be produced than can be dealt with by homeostatic

transported to the liver in plasma, the NEFA being

buffering mechanisms, depleting the plasma bicarbonate

protein bound, predominantly to albumin. Glycerol

concentration, which therefore falls (see Chapter 4).

enters the hepatic gluconeogenic pathway at the

The plasma glucose concentration is maintained

triose phosphate stage; the glucose synthesized can be

principally by hepatic gluconeogenesis, but during

released from these cells, thus minimizing the fall in

prolonged starvation, such as that in anorexia nervosa or

glucose concentrations.

during childhood, ketotic hypoglycaemia may occur. The

BRAIN

G6P

Acetyl CoA

CO 2 + H 2 O

Glucose

KETONES + H +

Triglyceride

G6P

GLYCOGEN

Triose-P

Glycerol

KETONES + H +

+

FA

NEFA

Pyruvate

Acetyl CoA

LIVER

ADIPOSE TISSUE

Figure 12.6 Intermediary metabolism during fasting: ketosis. CoA, coenzyme A; FA, fatty acid; G6P,

glucose-6-phosphate; NEFA, non-esteri?ed fatty acid.

Carbohydrate metabolism

180

BRAIN

MUSCLE

G6P

Insulin

GLYCOGEN

INTESTINE

CO 2 + H 2 O

G6P

GLUCOSE

Glucose

Insulin

Insulin

G6P

G6P

GLYCOGEN

Triose-P

Triose-P

Acetyl CoA

Fatty acid + Glycerol-3-P

Fatty acid + Glycerol-3-P

Glycerol

Triglyceride

TRIGLYCERIDE

VLDL

LIVER

ADIPOSE TISSUE

Figure 12.5 Post-prandial metabolism of glucose. CoA, coenzyme A; G6P, glucose-6-phosphate; Glycerol-3-P,

glycerol-3-phosphate; Triose-P, triose phosphate or glyceraldehyde 3-phosphate; VLDL, very low-density lipoprotein.

stimulates the b -cells of the pancreas to secrete insulin.

these actions are impaired. Both muscle and adipose

tissue store the excess post-prandial glucose, but the

Insulin may further enhance hepatic and muscle

mode of storage and the function of the two types of

glycogenesis. More importantly, entry of glucose into

cell are very different, as will be shown later.

adipose tissue and muscle cells, unlike that into liver and

brain, is stimulated by insulin and, under physiological

Ketosis

conditions, the plasma glucose concentration falls to

Adipose tissue and the liver

near fasting levels. Conversion of intracellular glucose

Adipose tissue triglyceride is the most important long-

to G6P in adipose and muscle cells is catalysed by the

term energy store in the body. Greatly increased use

enzyme hexokinase, which, because its affinity for

of fat stores, for example during prolonged fasting,

glucose is greater than that of hepatic glucokinase,

is associated with ketosis. Adipose tissue cells, acting

ensures that glucose enters the metabolic pathways in

in conjunction with the liver, convert excess glucose

these tissues at lower extracellular concentrations than

to triglyceride and store it in this form rather than

those in the liver. The relatively high insulin activity

as glycogen. The components are both derived from

after a meal also inhibits the breakdown of triglyceride

glucose, fatty acids from the glucose entering hepatic

(lipolysis) and protein (proteolysis). If there is relative

cells and glycerol from that entering adipose tissue cells.

or absolute insulin deficiency, as in diabetes mellitus,

Hyperglycaemia and diabetes mellitus

183

During gluconeogenesis, hydrogen ions are reused.

hepatic and renal gluconeogenesis from lactate

Under aerobic conditions, the liver consumes much

cannot occur anaerobically,

more lactate than it produces.

anaerobic glycolysis is stimulated because the

The physiological accumulation of lactic acid during

falling adenosine triphosphate (ATP) levels cannot

muscular contraction is a temporary phenomenon and

be regenerated by the TCA cycle under anaerobic

rapidly disappears at rest, when slowing of glycolysis

conditions.

allows aerobic processes to `catch up'.

The combination of impaired gluconeogenesis and

increased anaerobic glycolysis converts the liver from

Pathological lactic acidosis

an organ that consumes lactate and H + to one that

Lactic acid, produced by anaerobic glycolysis, may either

generates large amounts of lactic acid. Severe hypoxia,

be oxidized to CO 2 and water in the TCA cycle or be

for example following a cardiac arrest, causes marked

reconverted to glucose by gluconeogenesis in the liver.

lactic acidosis. If diabetic ketoacidosis is associated with

Both the TCA cycle and gluconeogenesis need oxygen;

signi?cant volume depletion, this hypoxic syndrome

anaerobic glycolysis is a non-oxygen-requiring pathway.

may aggravate the acidosis. (See Chapter 4 for a further

Pathological accumulation of lactate may occur because:

discussion of lactic acidosis.)

The glycolytic pathway as well as the TCA cycle are

production is increased by an increased rate of

summarized in Figures 12.1 and 12.2.

anaerobic glycolysis,

use is decreased by impairment of the TCA cycle or

impairment of gluconeogenesis.

HYPERGL

YCAEMIA AND DIABETES

MELLITUS

Tissue hypoxia (Fig. 12.8) due to the poor tissue

Hyperglycaemia may be due to:

perfusion of the `shock' syndrome is usually the most

common cause of lactic acidosis. Hypoxia increases

intravenous infusion of glucose-containing fluids,

plasma lactate concentrations because:

severe stress (usually a transient effect) such as

trauma, myocardial infarction or cerebrovascular

the TCA cycle cannot function anaerobically and

accidents,

oxidation of pyruvate and lactate to CO 2 and water

diabetes mellitus or impaired glucose regulation.

is impaired,

GLYCOGEN

G6P

G6P

GLYCOGEN

Pyruvate

LACTATE + H +

LACTATE + H +

Pyruvate

LACTATE+ H +

MUSCLE

LIVER

Figure 12.8 Metabolic pathways during tissue hypoxia. G6P, glucose-6-phosphate.

Carbohydrate metabolism

184

Diabetes mellitus

There is a spectrum of disorders ranging from mainly

insulin resistance with relative insulin deficiency to a

Diabetes mellitus is caused by an absolute or relative

predominantly secretory defect with insulin resistance.

insulin deficiency. It has been defined by the World

Health Organization (WHO), on the basis of

Other specific types of diabetes mellitus

laboratory findings, as a fasting venous plasma glucose

A variety of inherited disorders may be responsible for

concentration of 7.0 mmol/L or more (on more than one

the syndrome, either by reducing insulin secretion or by

occasion or once in the presence of diabetes symptoms)

causing relative insulin deficiency because of resistance

or a random venous plasma glucose concentration

to its action or of insulin receptor defects, despite high

of 11.1 mmol/L or more. Sometimes an oral glucose

plasma insulin concentrations.

tolerance test (OGTT) may be required to establish the

diagnosis in equivocal cases. The interpretation of this

Genetic defects of b -cell function

test is shown below, but, briefly, diabetes mellitus can be

Maturity-onset diabetes of the young (MODY):

diagnosed if the venous plasma glucose concentration

- MODY 1: mutation of the hepatocyte nuclear

is 7.0 mmol/L or more (fasting) and/or 11.1 mmol/L

factor ( HNF4A ) gene,

or more 2 h after the oral ingestion of the equivalent

- MODY 2: mutation of the glucokinase gene,

of 75 g of anhydrous glucose. Diabetes mellitus can be

- MODY 3: mutation of the HNF1A gene.

classified into the following categories.

Some cases are thought to be point mutations in

Type 1 diabetes mellitus

mitochondrial deoxyribonucleic acid (DNA) associated

Previously called insulin-dependent diabetes mellitus,

with diabetes mellitus and deafness and are usually

this is the term used to describe the condition in patients

autosomal dominant.

for whom insulin therapy is essential because they are

Genetic defects of insulin action

prone to develop ketoacidosis. It usually presents during

Type A insulin resistance (insulin receptor defect),

childhood or adolescence. Most of these cases are due to

for example leprechaunism, lipoatrophy and

immune-mediated processes and may be associated with

Rabson-Mendenhall syndrome.

other autoimmune disorders such as Addison's disease,

vitiligo and Hashimoto's thyroiditis. It has been suggested

Insulin deficiency due to pancreatic disease

that many cases follow a viral infection that has damaged

Chronic pancreatitis.

the b -cells of the pancreatic islets. Individuals most

Pancreatectomy.

at risk are those with human leucocyte antigen (HLA)

Haemochromatosis.

types DR3 and DR4 of the major histocompatibility

Cystic fibrosis.

complex. Autoantibodies to islet cells, insulin, tyrosine

Endocrinopathies

phosphatases IA-2 and IA-2 b and glutamic decarboxylase

(GAD) are found in about 90 per cent of cases. There

Relative insulin deficiency, due to excessive GH

is a form of type 1 diabetes called idiopathic diabetes

(acromegaly), phaeochromocytoma, glucocorticoid

mellitus that is not autoimmune mediated but is strongly

secretion (Cushing's syndrome).

inherited and more common in black and Asian people.

Drugs

The insulin requirement of affected people can fluctuate

Thiazide diuretics.

widely and the cause is unknown. There is also LADA

Interferon- a .

(latent autoimmune diabetes of adults), sometimes

Glucocorticoids.

called slow-onset type 1 diabetes.

Infections

Type 2 diabetes mellitus

Septicaemia.

Previously called non-insulin-dependent diabetes

Congenital rubella.

mellitus, this is the most common variety worldwide

Cytomegalovirus.

(about 90 per cent of all diabetes mellitus cases). Patients

Rare forms of autoimmune-mediated diabetes

are much less likely to develop ketoacidosis than those

Anti-insulin receptor antibodies.

with type 1 diabetes, although insulin may sometimes

Stiff man syndrome, with high levels of GAD

be needed. Onset is most usual during adult life; there

autoantibodies.

is a familial tendency and an association with obesity.

Hyperglycaemia and diabetes mellitus

185

Genetic syndromes associated with diabetes

homeostasis and diabetes mellitus. The definition is

that the fasting venous plasma glucose is 6.1 mmol/L

Down's syndrome.

or more but less than 7.0 mmol/L, and less than

Turner's syndrome.

7.8 mmol/L 2 h after an OGTT.

Klinefelter's syndrome.

Myotonic dystrophy.

Subjects at risk of developing diabetes mellitus

Gestational diabetes mellitus

A strong family history of diabetes mellitus may suggest

In the UK, about 4-5 per cent of pregnancies are

that an individual is at risk of developing diabetes

complicated by gestational diabetes mellitus (GDM).

mellitus (particularly type 2), as may a family history

It is associated with increased fetal abnormalities,

of GDM, IGT or IFG. Those with predisposing HLA

for example high birthweight, cardiac defects and

types and autoimmune disease may be susceptible

polyhydramnios. In addition, birth complications,

to developing type 1 diabetes. Type 2 diabetes is

maternal hypertension and the need for caesarean

more common in certain racial groups, such as Afro-

section may occur. If maternal diet/lifestyle factors fail

Caribbeans, South Asians and Pacific Islanders. One of

to restore glucose levels, insulin is usually required to

the reasons why type 2 diabetes is on the increase is the

try to reduce the risk of these complications.

increasing tendency to obesity and central adiposity in

Women at high risk for GDM include those who

urbanized and more sedentary populations consuming

have had GDM before, have previously given birth to a

high-calorie diets.

high-birthweight baby, are obese, have a family history of

The thrifty phenotype (Barker-Hales) hypothesis

diabetes mellitus and/or are from high-risk ethnic groups,

proposes that nutritional de?ciency in fetal and early

for example black or South Asian. These women should

infancy associated with low birthweight increases

be screened at the earliest opportunity and, if normal,

the risk of developing type 2 diabetes and insulin

retested at about 24-28 weeks, as glucose tolerance

resistance.

progressively deteriorates throughout pregnancy. In some

units 50 g oral glucose is used and the blood glucose is

Insulin resistance syndrome or metabolic syndrome

sampled at 1 h - plasma glucose of more than or equal to

It has been recognized that certain coronary heart disease

7.8 mmol/L being diagnostic (O'Sullivan's screening test

risk factors occur together. There is an aggregation of

for gestational diabetes). If fasting venous plasma glucose

lipid and non-lipid risk factors of metabolic origin.

is 7.0 mmol/L or more and/or the random measurement

A particular cluster is known as the metabolic syndrome,

gives a concentration of 11.1 mmol/L or more (some

syndrome X or Reaven's syndrome and is closely linked

doctors prefer to use a lower cut-off of about 9.0 mmol/L

to insulin resistance. One definition is the presence of

in pregnancy), the woman has GDM. In equivocal cases,

three or more of the following features:

an OGTT is indicated. Six weeks post partum, the woman

Abdominal obesity (waist circumference):

should be reclassi?ed with a repeat OGTT.

- male more than 102 cm (40 in),

Impaired glucose tolerance

- female more than 88 cm (35 in).

The WHO definition of impaired glucose tolerance

Fasting plasma triglycerides more than 1.7 mmol/L.

(IGT) is a fasting venous plasma glucose concentration

Fasting plasma high-density lipoprotein (HDL)

of less than 7.0 mmol/L and a plasma glucose

cholesterol:

concentration between 7.8 mmol/L and 11.1 mmol/L

- male less than 1.0 mmol/L,

2 h after an OGTT. Some patients with IGT develop

- female less than 1.3 mmol/L,

diabetes mellitus later and may require an annual OGTT

Blood pressure more than or equal to 130/85 mmHg.

to monitor for this. However, because of the increased

Fasting blood glucose more than 5.5 mmol/L.

risk of vascular complications, secondary causes of IGT

Plasma levels of insulin would be expected to be

should be sought, dietary advice given, if necessary, and

raised, that is, hyperinsulinaemia. Other associated

the patient followed up. In pregnancy IGT is treated as

features may include polycystic ovary syndrome, fatty

GDM because of the risks to the fetus.

liver, raised ?brinogen and plasminogen activator

Impaired fasting glucose

inhibitor 1 concentrations, renal sodium retention,

hyperuricaemia and dense low-density lipoprotein

Impaired fasting glucose (IFG), like IGT, refers to a

(LDL) particles (see Chapter 13).

metabolic stage intermediate between normal glucose

Carbohydrate metabolism

186

Metabolic features of diabetes mellitus

Long-term effects of diabetes mellitus

Vascular disease is a common complication of diabetes

Patients with type 1 diabetes tend to be diagnosed before

mellitus. Macrovascular disease due to abnormalities of

the age of 40 years, are usually lean and have experienced

large vessels may present as coronary artery, cerebrovascular

weight loss at the time of presentation. They may

or peripheral vascular insufficiency. The condition is

present with diabetic ketoacidosis. Conversely, patients

probably related to alterations in lipid metabolism and

with type 2 diabetes often present later, usually after the

associated hypertension. The most common cause of death

age of 40 years, and are often overweight or obese. The

is cardiovascular disease, including myocardial infarction.

presentation can be insidious and they may have had

Microvascular disease due to abnormalities of small

diabetes years before diagnosis.

blood vessels particularly affects the retina (diabetic

Hyperglycaemia

retinopathy) and the kidney (nephropathy); both may

If plasma glucose concentration exceeds about

be related to inadequate glucose control. Diabetes is

10 mmol/L, glycosuria would be expected. High urinary

one of the most common causes of patients requiring

glucose concentrations produce an osmotic diuresis and

renal dialysis. Microvascular disease of the kidney is

therefore polyuria. Cerebral cellular dehydration due to

associated with proteinuria.

hyperosmolality, secondary to hyperglycaemia, causes

Kidney disease is associated with several

thirst (polydipsia). A prolonged osmotic diuresis may

abnormalities, including proteinuria and progressive

cause excessive urinary electrolyte loss. These `classic'

renal failure. Diffuse nodular glomerulosclerosis

symptoms are suggestive of diabetes mellitus.

(Kimmelstiel-Wilson lesions) may cause the nephrotic

Diabetic patients on insulin may show the

syndrome. The presence of small amounts of albumin

following conditions. The `dawn' phenomenon is the

in the urine (microalbuminuria) is associated with an

physiological response of the elevation of blood glucose

increased risk of developing progressive renal disease,

concentration in the early morning prior to breakfast

which may sometimes be prevented by more stringent

due to nocturnal spikes in GH concentration and a rise

plasma glucose and blood pressure control. The renal

in plasma cortisol concentration that increase hepatic

complications may be partly due to the increased

gluconeogenesis. Conversely, in some diabetic patients

glycation of structural proteins in the arterial walls

nocturnal hypoglycaemia may evoke a rebound

supplying the glomerular basement membrane; similar

counter-regulatory hyperglycaemia called the Somogyi

vascular changes in the retina may account for the high

phenomenon. Patient blood glucose checking at 02.00-

incidence of diabetic retinopathy. Glycation of protein

04.00 h, or continuous glucose monitoring if available,

in the lens may cause cataracts.

may distinguish these conditions, as the Somogyi

Infections are also more common in diabetic

phenomenon reveals hypoglycaemia. It is sometimes

patients, for example urinary tract or chest infections,

possible to ameliorate these conditions by giving

cellulitis and candida. Diabetic neuropathy can occur,

intermediate-acting insulin before bedtime.

which can be peripheral symmetric sensory, peripheral

Abnormalities in lipid metabolism

painful, acute mononeuropathies or autonomic. It

These may be secondary to insulin deficiency. Lipolysis

has been suggested that sorbitol is implicated in the

is enhanced and plasma NEFA concentrations rise.

aetiology of diabetic neuropathy through the action of

In the liver, NEFAs are converted to acetyl CoA and

aldolase reductase. Erectile dysfunction is also relatively

ketones, or are re-esterified to form endogenous

common and in some cases may be partly neurologically

triglycerides and incorporated into VLDLs; the latter

mediated.

accumulate in plasma because lipoprotein lipase, which

Diabetic ulcers, for example of the feet, can lead to

is necessary for VLDL catabolism, requires insulin for

gangrene and amputation. The ulcers can be ischaemic,

optimal activity. High-density lipoprotein cholesterol

neuropathic or infective. The joints can also be affected,

concentration tends to be low in type 2 diabetes. If

for example Charcot's joints. Other features of diabetes

insulin deficiency is very severe, there may also be

mellitus are skin disorders, such as necrobiosis lipoidica,

chylomicronaemia. The rate of cholesterol synthesis is

and abscesses.

also increased, with an associated increase in plasma

Principles of management of diabetes mellitus

LDL concentrations. Consequently, patients with

The management of diabetes mellitus is considered

diabetes may show high plasma triglyceride, raised

briefly, although consulting a specialist text is

cholesterol and low HDL cholesterol concentrations.

Hyperglycaemia and diabetes mellitus

187

recommended if further information is required. Insulin

proximal tubular cells reabsorb most of the glucose

requirements vary in patients with type 1 diabetes. For

in the glomerular filtrate. Glycosuria, as defined

example, the dose may need to be increased during

above, occurs only when the plasma, and therefore

any illness or during pregnancy and reduced if there is

glomerular filtrate, concentrations exceed the tubular

increased activity or meals are missed.

reabsorptive capacity. This may be because the plasma

In patients with type 2 diabetes, plasma glucose

and glomerular filtrate concentrations are more than

concentrations may be controlled by diet, associated

about 10 mmol/L, and therefore the normal tubular

with weight reduction, and increased physical activity,

reabsorptive capacity is significantly exceeded. Very

but insulin may be required during periods of stress

rarely, if the glomerular filtration rate is much reduced,

or pregnancy. In this group insulin secretion can be

there may be no glycosuria despite plasma glucose

stimulated by the sulphonylurea drugs, such as gliclazide,

concentrations more than 10 mmol/L. A diagnosis of

glipizide, glibenclamide or glimepiride. Biguanides,

diabetes mellitus should never be made on the basis of

usually metformin, can also be used and are particularly

glycosuria.

useful in obese patients. Metformin decreases intestinal

Blood glucose

glucose absorption and hepatic gluconeogenesis as well

Blood glucose concentrations may be measured using

as increasing tissue insulin sensitivity. Metformin can

glucose testing reagent strips. The colour change of

inhibit oxidative phosphorylation, which can, under

the strip can be assessed visually or by using a portable

certain circumstances, lead to lactic acid accumulation.

glucose meter and the reaction often involves an enzyme

Acarbose delays post-prandial absorption of glucose by

determination of glucose, for example glucose oxidase.

inhibiting a -glucosidase.

Meters should ideally be overseen by laboratory staff

Other oral agents are the thiazolidinediones or

expert in point of care testing (see Chapter 30). Although

`glitazones', for example rosiglitazone and pioglitazone,

the measurement of blood glucose concentrations

which activate g -peroxisome proliferator-activated

involves the discomfort of several skin punctures,

receptors and which can reduce insulin resistance

many motivated patients are able to adjust their insulin

by a number of metabolic pathways, some of which

dose more accurately based on these results than on

involve increasing the transcription of nuclear proteins

those obtained by testing their urine. This method of

that control free fatty acid and tissue glucose uptake.

testing is also useful in the detection of hypoglycaemia.

Repaglinide is a meglitinide that increases insulin release

For patients who do not like blood testing, urinary

from pancreatic b -cells and enhances tissue insulin

glucose testing can be used, but of course cannot detect

sensitivity. The incretins are gastrointestinal hormones

hypoglycaemia and is dependent on the renal glucose

that increase insulin release from the pancreas after

threshold.

eating, for example glucagon-like peptide (GLP-1)

Glycated haemoglobin

and gastric inhibitory peptide (GIP). They are rapidly

Glycated haemoglobin (HbA 1c ) is formed by non-

inactivated by the enzyme dipeptidyl peptidase-4 (DPP-

enzymatic glycation of haemoglobin and is dependent

4). Incretin mimetics such as exenatide or liraglutide

on the mean plasma glucose concentrations and on the

or DPP-4 inhibitors such as sitagliptin, vildagliptin or

lifespan of the red cell; falsely low values may be found

saxagliptin are being used in type 2 diabetes mellitus..

in patients with haemolytic disease. Measurement of

It is now recognized that diabetes mellitus is not

blood HbA 1c may not reveal potentially dangerous

just a glucose disorder. It is important also to optimize

short-term swings and nor does HbA 1c detect

abnormal plasma lipids (see Chapter 13) and correct

hypoglycaemic episodes and thus plasma glucose

hypertension, particularly if there is microalbuminuria

estimations may also be useful.

or proteinuria (see Chapter 19).

This was expressed as a percentage of total blood

Monitoring of diabetes mellitus

haemoglobin concentration and gives a retrospective

Glycosuria

assessment of the mean plasma glucose concentration

during the preceding 6-8 weeks. The higher the

Glycosuria can be defined as a concentration of

glycated haemoglobin, the poorer the mean diabetic or

urinary glucose detectable using relatively insensitive,

glycaemic control.

but specific, screening tests. These tests often depend

Glycated haemoglobin used to be expressed in

on the action of an enzyme, such as glucose oxidase,

percentage units but now is expressed as mmol/mol

incorporated into a diagnostic strip. Usually, the

Carbohydrate metabolism

188

and conversion between the units is by the following

and less than 3.5 g/mol in females. An abnormal result

equation: IFCC-HbA 1c (mmol/mol) = [DCCT-HbA 1c

should be con?rmed in two out of three urine samples

(%) - 2.15]  10.929. HbA 1c tests are certi?ed by the

in the absence of other causes of proteinuria (see

National Glycohemoglobin Standardization Program

Chapter 19). Apart from being predictive of diabetic

(NGSP) to standardize them against the results of

renal complications, urinary albumin excretion is also

the 1993 Diabetes Control and Complications Trial

associated with increased vascular permeability and

(DCCT) but now are expressed as IFCC (International

enhanced risk of cardiovascular disease.

Federation of Clinical Chemistry) units. Intervention

Optimization of glycaemic control can slow the

trials for type 1 and type 2 diabetes have shown that

progression of microalbuminuria, as can treating

trying to optimize glycaemic control, as judged by HbA 1c ,

hypertension. Some recommend a target blood

to about 7 per cent (or above 53 mmol/mol) reduces

pressure lower than 140/80 mmHg in type 2 diabetes, or

the risk of microvascular diabetic complications.

135/75 mmHg or lower if microalbuminuria is present.

The blood pressure targets are usually more aggressive

Fructosamine

in type 1 diabetes, partly as the lifetime risk of overt

The measurement of plasma fructosamine concentrations

nephropathy is greater. Angiotensin-converting

may be used to assess glucose control over a shorter

enzyme (ACE) inhibitor therapy, such as lisinopril

time course than that of HbA 1c (about 2-4 weeks), but

in type 1 diabetic patients with microalbuminuria,

the assay has methodological limitations. Fructosamine

can result in a decline in the albumin excretion rate;

reflects glucose bound to plasma proteins, predominantly

similar ?ndings have been shown with enalapril in

albumin, which has a plasma half-life of about 20 days

type 2 diabetes. This action of ACE inhibitors is only

but is problematic in patients with hypoalbuminaemia,

partially dependent on their blood pressure-lowering

for example due to severe proteinuria. This assay may

ability, and therefore they presumably also have other

sometimes be useful in pregnancy and also if haemoglobin

important renal protective actions. The angiotensin II

variants, for example HbS or HbC, exist that may interfere

receptor antagonists (ARAs), for example irbesartan

with certain HbA 1c assays.

and losartan, have also been shown to have renal

protective actions.

Blood ketones

Monitoring of blood ketones may have a place

Acute metabolic complications of diabetes mellitus

in the home management of type 1 diabetes. A

b -hydroxybutyrate below 0.60 mmol/L is normal,

Patients with diabetes mellitus may develop various

metabolic complications that require emergency treat-

whereas values between 0.60 mmol/L and 1.0 mmol/L

ment, including coma, and these include the following.

may necessitate more insulin, and concentrations

greater than 1.0 mmol/L a warning to seek medical

Hypoglycaemia

advice.

This is probably the most common cause of coma seen

Urinary albumin determination and diabetic nephropathy

in diabetic patients. Hypoglycaemia is most commonly

caused by accidental overadministration of insulin or

One of the earliest signs of diabetic renal dysfunction

sulphonylureas or meglitinides. Precipitating causes

is the development of small amounts of albumin in the

include too high a dose of insulin or hypoglycaemic

urine, called microalbuminuria. Untreated, this can

drug; conversely, the patient may have missed a meal or

progress to overt albuminuria or proteinuria (more

taken excessive exercise after the usual dose of insulin

than 300 mg/day), impaired renal function and finally

or oral hypoglycaemic drugs.

end-stage renal failure.

Hypoglycaemia is particularly dangerous, and

Microalbuminuria is de?ned as a urinary albumin

some patients lack awareness of this; that is to say,

excretion of 30-300 mg/day or 20-200 æg/min. An

they lose warning signs such as sweating, dizziness

albumin concentration less than 30 mg/day or less than

and headaches. Driving is a major hazard under such

20 æg/min is de?ned as normoalbuminuria. A random

circumstances. Patients should monitor their own

urine sample or timed overnight collection can be

blood glucose closely, carry glucose preparations

useful to assess urinary albumin excretion, although

to abort severe hypoglycaemia and avoid high-risk

the standard test is the urinary albumin to creatinine

activities during which hypoglycaemic attacks could

ratio (ACR), which avoids a timed urine collection.

be dangerous.

This should normally be less than 2.5 g/mol in males

Hyperglycaemia and diabetes mellitus

189

CASE 1

CASE 2

A 34-year-old woman with known type 1 diabetes

A 24-year-old woman presented to the casualty

mellitus was admitted to hospital following a `black

department in a coma. The relevant biochemical

out' while driving. She had recently increased her

results were as follows:

insulin dose because she felt unwell with `flu' but

Plasma

unwisely had missed two meals during the day. The

Sodium 130 mmol/L (135-145)

results of some of her biochemistry tests were as

Potassium 5.9 mmol/L (3.5-5.0)

follows:

Bicarbonate 10 mmol/L (24-32)

Plasma

Chloride 92 mmol/L (95-105)

Sodium 135 mmol/L (135-145)

Glucose 35 mmol/L (5.5-11.1)

Potassium 4.0 mmol/L (3.5-5.0)

pH 7.10 (7.35-7.45)

Bicarbonate 23 mmol/L (24-32)

P a CO 2 3.1 kPa (4.6-6.0)

Urea 5.4 mmol/L (2.5-7.0)

P a O 2 11.1 kPa (9.3-13.3)

Creatinine 100 æmol/L (70-110)

Urine was positive for ketones.

Glucose 1.5 mmol/L (5.5-11.1)

DISCUSSION

pH 7.43 (7.35-7.45)

The patient was shown to have type 1 diabetes

P a CO 2 5.3 kPa (4.6-6.0)

mellitus and had presented in diabetic ketoacidosis,

P a O 2 12.1 kPa (9.3-13.3)

with hyperglycaemia, hyponatraemia, hyperkalaemia

and a metabolic acidosis.

DISCUSSION

The blood glucose shows hypoglycaemia, secondary

to the patient having increased her insulin dose

although euglycaemic diabetic ketoacidosis has been

despite having missed meals. Hypoglycaemia can

described when plasma glucose concentrations are only

present with neurological impairment, including

slightly elevated.

impaired memory, loss of consciousness and coma.

Hyperglycaemia causes glycosuria and hence an

This can be treated in the emergency situation by

osmotic diuresis. Water and electrolyte loss due to

giving glucose intravenously to avoid irreversible

vomiting, which is common in this syndrome, increases

neurological damage. It is important for patients on

?uid depletion. There may be haemoconcentration and

insulin to monitor their own blood glucose closely,

reduction of the glomerular ?ltration rate enough to

particularly if they wish to drive.

cause uraemia due to renal circulatory insuf?ciency.

The extracellular hyperosmolality causes a shift of water

out of the cellular compartment and severe cellular

Diabetic ketoacidosis

dehydration occurs. Loss of water from cerebral cells is

probably the reason for the confusion and coma. Thus

Diabetic ketoacidosis may be precipitated by infection,

there is both cellular and extracellular volume depletion.

acute myocardial infarction or vomiting. The patient

The rate of lipolysis is increased because of decreased

who reasons `no food, therefore no insulin' could

insulin activity; more free fatty acids are produced than

mistakenly withhold insulin. In the absence of insulin,

can be metabolized by peripheral tissues. The free fatty

there is increased lipid and protein breakdown,

acids are either converted to ketones by the liver or,

enhanced hepatic gluconeogenesis and impaired

of less immediate clinical importance, incorporated

glucose entry into cells.

as endogenous triglycerides into VLDL, sometimes

The clinical consequences of diabetic ketoacidosis

causing severe hypertriglyceridaemia (see Chapter 13).

are due to:

Hydrogen ions, produced with ketones other than

hyperglycaemia causing plasma hyperosmolality,

acetone, are buffered by plasma bicarbonate. However,

metabolic acidosis,

when their rate of production exceeds the rate of

glycosuria.

bicarbonate generation, the plasma bicarbonate falls.

Plasma glucose concentrations are usually in the

Hydrogen ion secretion causes a fall in urinary pH.

range 20-40 mmol/L, but may be considerably higher,

The deep, sighing respiration (Kussmaul's respiration)

Carbohydrate metabolism

190

Table 12.4 Clinical and biochemical ?ndings in a

and the odour of acetone on the breath are classic

patient presenting with diabetic ketoacidosis

features of diabetic ketoacidosis.

Plasma potassium concentrations may be raised,

Findings

Underlying abnormality

secondarily to the metabolic acidosis, before treatment

Clinical

is started. This is due to failure of glucose entry into

Confusion and later coma

Hyperosmolality

cells in the absence of insulin and because of the low

Hyperventilation (Kussmaul's respiration)

Metabolic acidosis

glomerular ?ltration rate. Despite hyperkalaemia,

there is a total body de?cit due to increased urinary

Signs of volume depletion

Osmotic diuresis

potassium loss in the presence of an osmotic diuresis.

Biochemical

During treatment, plasma potassium concentrations

Plasma

may fall as potassium re-enters cells, sometimes causing

Hyperglycaemia

Insulin de?ciency

severe hypokalaemia unless potassium is prescribed.

Low plasma bicarbonate

Metabolic acidosis

Plasma sodium concentrations may be low

Initial hyperkalaemia

Intracellular potassium

(hyponatraemia) or low-normal at presentation, partly

moves out

because of the osmotic effect of the high extracellular

Mild uraemia

Decreased glomerular

glucose concentration, which draws water from the cells and

?ltration rate

dilutes the sodium. In the presence of a very high plasma

Urine

glucose concentration, a normal or raised plasma sodium

Glycosuria

Insulin de?ciency

concentration is suggestive of signi?cant water depletion.

Ketonuria

Insulin de?ciency

If there is severe hyperlipidaemia, the possibility of

pseudohyponatraemia must be considered (see Chapter

2). When insulin is given, gluconeogenesis is inhibited,

glucose enters cells and sodium-free water follows along

of the symptoms, including those of confusion and

the osmotic gradient. If plasma sodium concentrations

coma, are related to it. However, the term `hyperosmolal'

rise rapidly, the patient may remain confused or even

coma or `pre-coma' is usually confined to a condition

comatose as long as the plasma osmolality remains

in which there is marked hyperglycaemia but no

signi?cantly raised, despite a satisfactory fall in plasma

detectable ketoacidosis. The reason for these different

glucose concentration. This may also occur if isosmolar

presentations is not clear. It has been suggested that

or stronger saline solutions are given inappropriately.

insulin activity is sufficient to suppress lipolysis but

Hyperphosphataemia followed by hypophosphataemia

insufficient to suppress hepatic gluconeogenesis or to

as plasma phosphate concentrations parallel those of

facilitate glucose transport into cells.

potassium may persist for several days after recovery from

Hyperosmolal non-ketotic (HONK) coma now

diabetic coma. Similarly, hypermagnesaemia can result,

may be referred to as hyperosmolar hyperglycaemic

partly because of the acidosis.

state (HHS) and may be of sudden onset. It is

Plasma and urinary amylase activities may be

more common in older patients. Plasma glucose

markedly elevated and, even in the presence of abdominal

concentrations may exceed 50 mmol/L. The effects of

pain mimicking an `acute abdomen', do not necessarily

glycosuria are as described above, but hypernatraemia

indicate acute pancreatitis. In some patients the amylase

due to predominant water loss is more commonly

is of salivary rather than pancreatic origin. Some plasma

found than in ketoacidosis and aggravates the plasma

creatinine assays cross-react with ketones, resulting in a

hyperosmolality. Cerebral cellular dehydration, which

spurious plasma creatinine elevation. Sometimes severe

contributes to the coma, may also cause hyperventilation,

hypertriglyceridaemia and chylomicronaemia result,

and a respiratory alkalosis, although sometimes plasma

due to reduced lipoprotein lipase activity in the face

lactic acid may rise, evoking a metabolic acidosis and

of insulin de?ciency. A summary of the usual clinical

thus a mixed acid-base disturbance may occur. There

and biochemical ?ndings in a patient presenting with

may also be an increased risk of thrombosis.

diabetic ketoacidosis is shown in Table 12.4.

Lactic acidosis

Hyperosmolal non-ketotic coma

Lactic acidosis can cause a high anion gap metabolic

In diabetic ketoacidosis there is always plasma

acidosis and coma. It may be due to the use of

hyperosmolality due to the hyperglycaemia, and many

metformin in certain situations, such as high doses in

Hyperglycaemia and diabetes mellitus

191

the very elderly, those with renal, liver or cardiac failure

next hour and then 2 h and repeated at 4 h. Monitoring

or those dehydrated or undergoing imaging tests with

central venous pressure may be useful to assess fluid

contrast media (see Chapter 4).

replacement. Dextrose-saline may be used when the

plasma glucose concentration is less than 15 mmol/L.

Other causes of coma in patients with diabetes mellitus

If the plasma glucose concentration is more than

In addition to the comas described above, a patient

20 mmol/L, 10 U soluble insulin should be given. A

with diabetes mellitus may present with other comas:

sliding insulin scale should be instigated. Insulin is

given either by continuous intravenous infusion or

Cerebrovascular accidents are relatively common in

by intermittent intramuscular injections, as soon as

diabetic patients because of the increased incidence

the plasma glucose and potassium concentrations

of vascular disease.

are known. Once the patient is eating, subcutaneous

Diabetic patients can, of course, have any other

insulin can be given instead.

coma, for example drug overdose.

If the metabolic acidosis is very severe (pH less than

Diabetic patients are also more at risk of diabetic

7.0), bicarbonate may be infused, but only until the

nephropathy and renal failure and thus uraemic coma.

blood pH rises to between about 7.15 and 7.20. It is

The assessment of a diabetic patient presenting in

unnecessary and often dangerous to correct the plasma

coma or pre-coma is outlined in Table 12.5.

bicarbonate concentration completely; it rapidly returns

to normal following adequate ?uid and insulin therapy.

Principles of treatment of diabetic coma

Remember that 8.4 per cent sodium bicarbonate is

Only the outline of treatment will be discussed. For

very hyperosmolar and may cause hypernatraemia and

details of management, the reader should consult a

aggravate hyperosmolality. A rapid rise in the blood

textbook of medical emergencies.

pH may aggravate the hypokalaemia associated with

treatment.

Hypoglycaemia

The plasma potassium concentration should be

Hypoglycaemic coma needs prompt glucose replacement

measured before insulin is given. It is almost always

to avoid irreversible brain damage, for example 50 mL

raised at presentation due to the metabolic acidosis and

of 20 per cent glucose intravenously. If intravenous

reduced glomerular ?ltration rate, although total body

access is not an option, glucagon 1 mg can be given

potassium may be decreased. The plasma potassium

intramuscularly. Once the patient is awake, glucose-

concentration may fall rapidly once treatment is

containing drinks can be given.

started, and therefore it should be monitored frequently

Diabetic ketoacidosis

and potassium given as soon as it starts to fall. Usually

Repletion of fluid and electrolytes should be vigorous.

20 mmol/L potassium is given to each litre bag apart

A 0.9 per cent normal saline solution should be

from the ?rst litre and provided there is no oliguria or

administered, usually 1 L initially and then 1 L over the

hyperkalaemia. Diabetic ketoacidosis is severe if blood

Table 12.5 Clinical and biochemical features of a diabetic patient presenting in coma

Laboratory ?ndings

Plasma

Urine

Diagnosis

Clinical features

Glucose

Bicarbonate

Lactate

Creatinine

Ketones

Hypoglycaemia

Sweaty, drowsy

Low

N

N

N

Neg

Ketoacidosis

Volume depletion

High

Low

N

N or up

Pos

Hyperventilating

Hyperosmolar coma

Volume depletion

Very high

N or slightly low

N or up

N or up

Neg

May be hyperventilating

Lactic acidosis

Hyperventilating

Variable

Low

Up

N

Neg

Uraemia

Hyperventilating

Variable

Low

N or up

Up

Neg

Cerebrovascular accident

Neurological

May be raised

May be low

N

N

Neg

N, normal; Neg, negative; Pos, positive.

Carbohydrate metabolism

192

Hyperosmolal non-ketotic coma

ketones are greater than 6 mmol/L and the treatment

aim is for these to be less than 0.30 mmol/L.

The treatment of HONK coma is similar to that of

Urinary volume should be monitored; if it fails to

ketoacidosis. A sudden reduction of extracellular

rise despite adequate rehydration, further ?uid and

osmolality may be harmful, and it is important to

potassium should be given only if clinically indicated,

give small doses of insulin to reduce plasma glucose

and then with care. The risk of deep vein thrombosis is

concentrations slowly, for example 1 U/h. These patients

increased, in part due to dehydration, and thus heparin

are often very sensitive to the action of insulin. Hypo-

5000 U every 8 h subcutaneously can be given.

osmolal solutions are often used to correct volume

Clinical conditions such as infection that may have

depletion, but these too should be given slowly. Heparin

precipitated the coma should be sought and treated.

is usually given, as there is an increased risk of venous

Frequent monitoring of plasma glucose, potassium and

thrombosis.

sodium concentrations is essential to assess progress and

to detect developing hypoglycaemia, hypokalaemia or

Initial investigation of a diabetic patient presenting

hypernatraemia. Acid-base balance should also be assessed.

in coma

A diabetic patient may be in coma due to hyperglycaemia,

CASE 3

hypoglycaemia or any of the causes shown in Tables

12.4 and 12.5. After a thorough clinical assessment,

A 77-year-old man with known type 2 diabetes

proceed as follows:

mellitus presented to the casualty department feeling

drowsy. His home blood glucose monitoring had

Notify the laboratory that specimens are being taken

recently averaged about 25 mmol/L and a recent

and ensure that they are delivered promptly. This

glycated haemoglobin (HbA 1c ) result obtained by his

minimizes delays.

general practitioner was 12 per cent (108 mmol/mol).

Take blood immediately for estimation of:

The following blood results were returned in hospital:

- glucose,

- sodium and potassium,

Plasma

- urea and creatinine,

Sodium 160 mmol/L (135-145)

- bicarbonate,

Potassium 5.0 mmol/L (3.5-5.0)

- arterial blood gases.

Bicarbonate 21 mmol/L (24-32)

Do a drug screen for aspirin and paracetamol if

Urea 15 mmol/L (2.5-7.0)

concomitant drug overdose suspected.

Creatinine 130 æmol/L (70-110)

Determination of plasma lactate will help diagnose a

Glucose 65 mmol/L (5.5-11.1)

lactic acidosis (see Chapter 4).

Osmolality 380 mmol/kg (285-295)

Test a urine sample or blood for ketones.

pH 7.38 (7.35-7.45)

A rapid assessment of blood glucose concentration

P a CO 2 5.2 kPa (4.6-6.0)

may be obtained using a point-of-care (POCT)

P a O 2 11.8 kPa (9.3-13.3)

device, but results may be dangerously wrong so

Urine was negative for ketones.

these should always be checked against the results

DISCUSSION

obtained from the laboratory (see Chapter 30).

The patient was found to be in a hyperosmolal non-

If severe hypoglycaemia is suspected on clinical

ketotic (HONK) diabetic coma. Note the severe

grounds or because of the results obtained using

hyperglycaemia, hypernatraemia and high plasma

reagent strips, glucose should be given immediately

osmolality and presentation in an elderly patient.

while waiting for the laboratory results. It is

HONK coma is associated with type 2 diabetes

less dangerous to give glucose to a patient with

mellitus. Ketoacidosis is usually absent, as there has

hyperglycaemia than to give insulin to a patient with

been no conversion to ketone metabolism. This is

hypoglycaemia.

more common in the elderly, and severe dehydration

The results of point-of-care testing (see Chapter 30)

is present and there is an increased risk of thrombotic

must be interpreted with caution.

events and focal neurological signs. Treatment is with

Also look for precipitating causes such as acute

careful intravenous rehydration, insulin and heparin.

myocardial infarction or infection.

Hyperglycaemia and diabetes mellitus

193

Investigation of suspected diabetes mellitus

Oral glucose tolerance test

Before starting this test, contact your laboratory: local

In most cases a diagnosis can be established from either

details may vary.

fasting or random blood glucose determinations. In

equivocal cases an OGTT may be required.

Procedure

The patient should be resting and should not smoke

Initial investigations

during the test.

The patient fasts overnight (for at least 10 h but

Blood for plasma glucose estimation should be taken if

not more than 16 h). Water, but no other beverage, is

a patient presents with symptoms of diabetes mellitus

allowed.

or glycosuria or if it is desirable to exclude the diagnosis,

A venous sample is withdrawn for plasma glucose

for example because of a strong family history.

estimation. If the glucose concentration is measured

Blood samples may be taken:

in whole blood, the results will be approximately

at least 10 h after a fast,

1.0 mmol/L lower.

at random,

A solution containing 75 g of anhydrous glucose

as part of an oral glucose load test.

in 300 mL of water is hyperosmolar, and not only

may cause nausea and occasionally vomiting and

Diabetes mellitus is con?rmed if one of the following

diarrhoea, but also, because of delayed absorption,

is present:

may affect the results of the test. It is therefore more

usual to give a solution of a mixture of glucose and

a fasting venous plasma concentration of 7.0 mmol/L

its oligosaccharides, because fewer molecules per unit

or more on two occasions or once with symptoms,

volume have less osmotic effect than the equivalent

a random venous plasma concentration of

amount of monosaccharide; the oligosaccharides are

11.1 mmol/L or more on two occasions or once with

all hydrolysed at the brush border, and the glucose

symptoms.

immediately enters the cells.

Diabetes mellitus is unlikely if the fasting venous

A solution that contains the equivalent of 75 g of

plasma glucose concentration is less than 5.5 mmol/L

anhydrous glucose is: 113 mL of Polycal made up to

on two occasions. Samples taken at random times after

approximately 300 mL with water.

meals are less reliable for excluding than for con?rming

This solution should be drunk slowly over a few

the diagnosis.

minutes. Further blood is taken 2 h after the ingestion

The indications for performing an OGTT to diagnose

of glucose.

diabetes mellitus may include:

Note that in the investigation of acromegaly, sampling

is half-hourly over the 2-h period (see Chapter 7).

fasting venous plasma glucose concentration

Interpretation of the OGTT is shown in Table

between 5.5 mmol/L and less than 7.0 mmol/L

12.6. There is controversy as to how best to interpret

- this is debatable as the WHO recommends an

the OGTT in pregnancy because of the differences in

OGTT only if fasting plasma glucose is greater than

maternal glucose metabolism, as stated earlier.

6.0 mmol/L,

The following factors may affect the result of the test:

random venous plasma concentration between

Previous diet No special restrictions are necessary if

7.0 mmol/L and less than 11.1 mmol/L,

the patient has been on a normal diet for 3-4 days.

a high index of clinical suspicion of diabetes mellitus,

However, if the test is performed after a period of

such as a patient at high risk of gestational diabetes

carbohydrate restriction, for example as part of a

with equivocal blood glucose results.

weight-reducing diet, this may cause abnormal glucose

The OGTT is sometimes also useful in the diagnosis

tolerance, probably because metabolism is adjusted to

of acromegaly (see Chapter 7).

the `fasted state' and so favours gluconeogenesis.

It has been suggested that an HbA 1c of greater than

Time of day Most OGTTs are performed in the

6.5 per cent is diagnostic of diabetes mellitus, but

morning and the reference values quoted are for this

this is not universally agreed as other factors such as

time of day. There is evidence that tests performed

haemoglobin variants and abnormal erythrocyte

in the afternoon yield higher plasma glucose

lifespan may affect HbA 1c levels.

concentrations and that the accepted `reference

Carbohydrate metabolism

194

Table 12.6 Interpretation of the oral glucose tolerance test (glucose mmol/L); venous plasma preferred

Venous plasma

Capillary whole blood

Venous whole blood

Fasting

2h

Fasting

2h

Fasting

2h

Diabetes mellitus unlikely

< 6.1

< 7.8

< 5.6

< 7.8

< 5.6

< 6.7

Impaired glucose tolerance

< 7.0

7.8-11.1

< 6.1

7.8-11.1

< 6.1

6.7-10.0

Impaired fasting glucose

6.1-6.9

< 7.8

5.6-6.0

< 7.8

5.6-6.0

< 6.7

ò 7.0

ò 11.1

ò 6.1

ò 11.1

ò 6.1

ò 10.0

Diabetes mellitus

values' may not be applicable. This may be due to a

Symptoms of hypoglycaemia may develop at higher

circadian variation in islet cell responsiveness.

concentrations if there has been a rapid fall from a

Drug Steroids, oral contraceptives and thiazide

previously raised value, when adrenaline secretion is

diuretics may impair glucose tolerance.

stimulated and may cause sweating, tachycardia and

agitation. As discussed earlier, cerebral metabolism

HYPOGL

YCAEMIA (FIG. 12.9)

depends on an adequate supply of glucose from ECF,

and the symptoms of hypoglycaemia may resemble

By definition, hypoglycaemia is present if the plasma

those of cerebral hypoxia (neuroglycopenia). Faintness,

glucose concentration is less than 2.5 mmol/L in a

dizziness or lethargy may progress rapidly to coma and,

specimen collected into a tube containing an inhibitor

if untreated, permanent cerebral damage or death may

of glycolysis, for example fluoride oxalate. Blood

occur. Existing cerebral or cerebrovascular disease may

cells continue to metabolize glucose in vitro, and low

aggravate the clinical picture. Whipple's triad is de?ned

concentrations found in a specimen collected without

as hypoglycaemia, neuroglycopenic symptoms, and

such an inhibitor can be dangerously misleading

relief of these symptoms on raising the blood glucose.

(pseudohypoglycaemia).

Unexplained hypoglycaemia

Related to meals?

No

Yes

Measure plasma

Reactive hypoglycaemia?

insulin and C-peptide

Consider mixed meal test

Insulin O

Insulin

Insulin

Exogenous insulin?

C-peptide O

C-peptide

C-peptide O

Insulinoma or

Measure plasma

sulphonylurea

-hydroxybutyrate

drug or

(ketone body)

insulin receptor

antibodies

Raised

Low

Endocrine cause

Liver or kidney

or inborn error

failure or

of metabolism

non-pancreatic islet

(Box 12.1)

cell tumours

Figure 12.9 Algorithm for the investigation of hypoglycaemia in adults.

Hypoglycaemia

195

Hypoglycaemia is a disease manifestation and

hypoglycaemia, sometimes called Doege-Potter

not a diagnosis. There is no completely satisfactory

syndrome. Hypoglycaemia may be the presenting

classi?cation of its causes. However, one useful approach

feature. The mechanism is not always clear, but may

is to divide hypoglycaemia into (inappropriate)

sometimes be due to the secretion of insulin-like

hyperinsulinaemia, (appropriate) hypoinsulinaemia

growth factor 2 (IGF-2) or abnormal glycosylated big

and reactive hypoglycaemia (Box 12.1).

IGF-2. The IGF-2 suppresses GH and IGF-1. Tumours

secreting IGF-2 are characterized by an increased

Hypoinsulinaemic hypoglycaemia

plasma total IGF-2:IGF-1 ratio and low plasma insulin

Non-pancreatic tumours (non-islet cell tumours)

concentration.

Although carcinomas (especially of the liver) and

Endocrine causes

sarcomas have been reported to cause hypoglycaemia,

this occurs most commonly in association with

Hypoglycaemia may occur in hypothyroidism,

retroperitoneal tumours of mesenchymal origin,

pituitary or adrenal insufficiency. However, it is rarely

but also with lymphomas, haemangiopericytomas,

the presenting manifestation of these conditions.

liver carcinoma and leukaemia. Pleural spindle cell

tumours can be associated with a paraneoplastic

Impaired liver function

The functional reserve of the liver is so great that, despite

Box 12.1 Some causes of hypoglycaemia

its central role in the maintenance of plasma glucose

in adults

concentrations, hypoglycaemia is a rare complication

of liver disease. It may complicate very severe hepatitis,

Hyperinsulinaemic hypoglycaemia

hypoxic liver disease associated with congestive cardiac

Inappropriately high insulin concentrations due to:

failure or liver necrosis if the whole liver is affected.

Pancreatic tumour - insulinoma

Plasma IGF-1 concentration may be low.

Hyperplasia of the pancreatic islet cells

Insulin receptor antibodies

Renal failure

Autoimmune insulin syndrome

Renal failure can result in hypoglycaemia as the kidney,

Exogenous insulin

Sulphonylureas, meglitinides

like the liver, is a gluconeogenic organ.

Hypoinsulinaemic hypoglycaemia

Hyperinsulinaemic hypoglycaemia

Endocrine

Insulin or other drugs are probably the most common

Glucocorticoid de?ciency/adrenal insuf?ciency

causes. It is most important to take a careful drug

Severe hypothyroidism

Hypopituitarism

history. Unless the facts are deliberately concealed by the

Organ failure

patient, the offending drug should be easily identifiable.

Severe liver disease

Hypoglycaemia in a diabetic patient may be caused

End-stage renal disease

by accidental insulin overdosage, by changing insulin

Severe congestive cardiac failure

requirements, or by failure to eat after insulin has been

Malaria (particularly if taking quinine)

given. Self-administration for suicidal purposes or to

Some non-pancreatic islet cell tumours

gain attention is not unknown, and homicidal use is a

Insulin-like growth factor (IGF)-2-secreting tumours,

remote possibility. Sulphonylureas or meglitinides may

e.g. liver, adrenal, breast,

also induce hypoglycaemia, especially in the elderly.

mesenchymal, haemangiopericytomas

Hypoglycaemia due to exogenous insulin suppresses

Leukaemias, lymphomas, myeloma

Widespread metastases

insulin and C-peptide secretion. Measurement

of plasma C-peptide concentrations may help to

Reactive hypoglycaemia

Idiopathic

differentiate exogenous insulin administration, when

Post-gastric surgery

C-peptide secretion is inhibited, from endogenous

Alcohol induced

insulin secretion, when plasma C-peptide is raised,

Miscellaneous causes

whether it is from an insulinoma or following pancreatic

Von Gierke's disease (type 1 glycogen storage disease)

stimulation by sulphonylurea drugs.

Drugs, e.g. salicylates, quinine, haloperidol,

An insulinoma is usually a small, histologically

pentamidine, sulphonamides

benign primary tumour of the islet cells of the pancreas.

Carbohydrate metabolism

196

Reactive (functional) hypoglycaemia

CASE 4

Some people develop symptomatic hypoglycaemia

between 2 and 4 h after a meal or a glucose load. Loss

A 45-year-old woman was being investigated in the

of consciousness is very rare. Similar symptoms may

endocrine unit because of hypoglycaemic episodes,

follow a gastrectomy or bariatric gastric banding, when

which manifested as sweating and dizzy attacks and

rapid passage of glucose into the intestine, and rapid

which were relieved by sweet drinks. Her renal, liver

absorption, may stimulate excessive insulin secretion

and thyroid functions were all normal. Some of her

(`late dumping syndrome'). Reactive hypoglycaemia is

fasting biochemical results were as follows:

uncommon.

Plasma

Glucose 2.1 mmol/L (5.5-11.1)

Alcohol-induced hypoglycaemia

Insulin 168 pmol/L (10-50)

Hypoglycaemia may develop between 2 and 10 h

Insulin C-peptide 998 pmol/L (200-650)

after the ingestion of large amounts of alcohol. It is

A urinary sulphonylurea screen was negative.

found most often in undernourished subjects and

DISCUSSION

chronic alcoholics but may occur in young subjects

This patient has raised plasma insulin concentrations

when they first drink alcohol. Hypoglycaemia is

in the presence of fasting hypoglycaemia. She was

probably caused by the suppression of gluconeogenesis

subsequently shown to have an insulinoma. Note the

during the metabolism of alcohol. Differentiation of

raised plasma insulin and C-peptide concentrations

hypoglycaemia from alcoholic stupor may be impossible

in the presence of hypoglycaemia, suggesting the

unless the plasma glucose concentration is estimated. It

presence of endogenous insulin secretion (exogenous

may be necessary to infuse glucose frequently during

insulin administration would not be expected to be

treatment, until glycogen stores are repleted and plasma

associated with raised C-peptide concentrations).

glucose concentrations are stable.

Her symptoms and their relief by glucose-containing

See Chapter 26 for a discussion of hypoglycaemia in

drinks are classic indicators of hypoglycaemic

neonates and children.

episodes. Insulinomas can be associated with

Investigation of adult hypoglycaemia

multiple endocrine neoplasia (MEN) syndrome,

which should be excluded.

Some of the causes of hypoglycaemia are shown in Box

12.1 and can be divided into hyperinsulinaemic and

hypoinsulinaemic groups. The following scheme may

It may present at any age. Multiple tumours may occur

be useful in investigating hypoglycaemia. It is important

and may be part of the syndrome of multiple endocrine

to exclude pseudohypoglycaemia due to in vitro

neoplasia (MEN). As with other functioning endocrine

glucose metabolism, for example an old blood sample

tumours, hormone secretion is inappropriate and

or one not collected into fluoride oxalate anticoagulant.

usually excessive. C-peptide and proinsulin are released

Sometimes a cause may be evident from the medical

in parallel with insulin, and plasma concentrations

and drug histories and clinical examination.

are therefore inappropriately high in the presence

One of the most important tests in a patient with

of hypoglycaemia. Some insulinomas secrete just

proven hypoglycaemia is to measure the plasma insulin

proinsulin. Attacks of hypoglycaemia occur typically at

and C-peptide concentrations when the plasma glucose

night and before breakfast, associated with hunger, and

concentration is low. Plasma for these assays should

may be precipitated by strenuous exercise. Personality

be separated from cells immediately and the plasma

or behavioural changes may be the ?rst feature; some

stored at -20øC until hypoglycaemia has been proven.

patients present initially to psychiatrists.

These tests should differentiate exogenous insulin

Insulin antibodies can form in response to exogenous

administration and endogenous insulin production,

insulin, probably less so for human insulin than for

for example an insulinoma, from other causes of

animal types. Sometimes insulin antibodies form despite

hypoglycaemia.

the patient never having been exposed to exogenous

Raised plasma insulin concentrations and

insulin - autoimmune insulin syndrome (AIS).

suppressed plasma concentrations of C-peptide suggest

Insulin receptor antibodies may cause hypoglycaemia,

exogenous insulin administration (hyperinsulinaemic

although they sometimes lead to insulin resistance and

hypoglycaemia). Conversely, a high plasma insulin

hyperglycaemia.