Document Sample
DEFINITION AND Powered By Docstoc
					                                DIABETES MELLITUS

Diabetes mellitus (DM) is a group of clinical syndrome characterized by hyperglycemia
resulting from defects in insulin secretion, insulin action, or both. The chronic
hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure
of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels.

Symptoms of marked hyperglycemia include polyuria, polydipsia, weight loss,
sometimes with polyphagia, and blurred vision. Impairment of growth and susceptibility
to certain infections may also accompany chronic hyperglycemia. Acute, life-threatening
consequences of uncontrolled diabetes are hyperglycemia with ketoacidosis (DKA) or
the nonketotic hyperosmolar syndrome(NKHS). Long-term complications of diabetes
include retinopathy with potential loss of vision; nephropathy leading to renal failure;
peripheral neuropathy with risk of foot ulcers, amputations, and Charcot joints; and
autonomic neuropathy causing gastrointestinal, genitourinary, and cardiovascular
symptoms and sexual dysfunction. Patients with diabetes have an increased incidence of
atherosclerotic cardiovascular, peripheral arterial, and cerebrovascular disease.
Hypertension and abnormalities of lipoprotein metabolism are often found in people with

The criteria for the diagnosis of diabetes are shown in Table 1. Three ways to diagnose
diabetes are possible, and each, in the absence of unequivocal hyperglycemia, must be
confirmed, on a subsequent day, by any one of the three methods given in Table 1. The
use of the hemoglobin A1c(A1C) for the diagnosis of diabetes is not recommended at this

Table 1—Criteria for the diagnosis of diabetes mellitus
1. Symptoms of diabetes (polyuria, polydipsia, and unexplained weight loss)     plus casual
plasma glucose concentration200 mg/dl (11.1 mmol/ l). Casual is defined as any time of
day without regard to time since last meal.
2. FPG 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h.
3. 2-h postload glucose 200 mg/dl (11.1 mmol/l) during an OGTT. The test should be
performed as described by WHO, using a glucose load containing the equivalent of 75 g
anhydrous glucose dissolved in water.
In the absence of unequivocal hyperglycemia, these criteria should be confirmed by
repeat testing on a different day. The third measure (OGTT) is not recommended for
routine clinical use.

Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) recognized an
intermediate group of subjects whose glucose levels, although not meeting criteria for
diabetes, are nevertheless too high to be considered normal. This group is defined as
having fasting plasma glucose (FPG) levels 100 mg/dl (5.6 mmol/l) but <126 mg/dl (7.0
mmol/l) or 2-h values in the oral glucose tolerance test (OGTT) of140 mg/dl (7.8
mmol/l) but<200 mg/dl (11.1 mmol/l).

The pathogenesis of DM is not yet clear. Several pathogenic processes are involved in the
development of diabetes. These range from autoimmune destruction of the -cells of the
pancreas with consequent insulin deficiency to abnormalities that result in resistance to
insulin action. The basis of the abnormalities in carbohydrate, fat, and protein metabolism
in diabetes is deficient action of insulin on target tissues. Deficient insulin action results
from inadequate insulin secretion and/or diminished tissue responses to insulin at one or
more points in the complex pathways of hormone action. Impairment of insulin secretion
and defects in insulin action frequently coexist in the same patient, and it is often unclear
which abnormality, if either alone, is the primary cause of the hyperglycemia.

The degree of hyperglycemia may change over time, depending on the extent of the
underlying disease process(figure 1). A disease process may be present but may not have
progressed far enough to cause hyperglycemia. The same disease process can cause
impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) without fulfilling
the criteria for the diagnosis of diabetes. In some individuals with diabetes, adequate
glycemic control can be achieved with weight reduction, exercise, and/or oral
glucoselowering agents. These individuals therefore do not require insulin. Other
individuals who have some residual insulin secretion but require exogenous insulin for
adequate glycemic control can survive without it. Individuals with extensive -cell
destruction and therefore no residual insulin secretion require insulin for survival. The
severity of the metabolic abnormality can progress, regress, or stay the same. Thus, the
degree of hyperglycemia reflects the severity of the underlying metabolic process and its
treatment more than the nature of the process itself.

Patients with IFG and/or IGT are now referred to as having ―pre-diabetes‖ indicating the
relatively high risk for development of diabetes in these patients. In the absence of
pregnancy, IFG and IGT are not clinical entities in their own right but rather risk factors
for future diabetes as well as cardiovascular disease. They can be observed as
intermediate stages in any of the disease processes.

IFG and IGT are associated with the metabolic syndrome, which includes obesity
(especially abdominal or visceral obesity), dyslipidemia of the high-triglyceride and/or
low-HDL type, and hypertension. It is worth mentioning that medical nutrition therapy
aimed at producing 5–10% loss of body weight, exercise, and certain pharmacological
agents have been variably demonstrated to prevent or delay the development of diabetes
in people with IGT; the potential impact of such interventions to reduce cardiovascular
risk has not been examined to date. Note that many individuals with IGT are euglycemic
in their daily lives. Individuals with IFG or IGT may have normalor near normal glycated
hemoglobin levels. Individuals with IGT often manifest hyperglycemia only when
challenged with the oral glucose load used in the standardized OGTT.
Figure 1—Disorders of glycemia: etiologic types and stages. Even after presenting in
ketoacidosis, these patients can briefly return to normoglycemia without requiring
continuous therapy (i.e., “honeymoon” remission); in rare instances, patients in these
categories (e.g., Vacor toxicity, type1 diabetes presenting in pregnancy) may require
insulin for survival.

Assigning a type of diabetes to an individual often depends on the circumstances present
at the time of diagnosis, and many diabetic individuals do not easily fit into a single class.
Thus, for the clinician and patient, it is less important to label the particular type of
diabetes than it is to understand the pathogenesis of the hyperglycemia and to treat it

Type 1 diabetes      The pathogenesis of this type is -cell destruction, usually leading to
absolute insulin deficiency. It has two subtypes: Immune-mediated diabetes and
Idiopathic diabetes.

Immune-mediated diabetes. This form of diabetes, which accounts for only 5–10% of
those with diabetes, previously encompassed by the terms insulin-dependent diabetes,
type I diabetes, or juvenile- onset diabetes, results from a cellular-mediated autoimmune
destruction of the -cells of the pancreas. Markers of the immune destruction of the
-cell include islet cell autoantibodies, autoantibodies to insulin, autoantibodies to
glutamic acid decarboxylase (GAD65), and autoantibodies to the tyrosine phosphatases
IA-2 and IA-2. Also,the disease has strong HLA associations, with linkage to the DQA
and DQB genes, and it is influenced by the DRB genes. These HLA-DR/DQ alleles can
be either predisposing or protective.

Autoimmune destruction of -cells has multiple genetic predispositions and is also
related to environmental factors that are still poorly defined. Although patients are rarely
obese when they present with this type of diabetes, the presence of obesity is not
incompatible with the diagnosis. These patients are also prone to other autoimmune
disorders such as Graves’ disease, Hashimoto’s thyroiditis, Addison’s disease, vitiligo,
celiac sprue, autoimmune hepatitis, myasthenia gravis, and pernicious anemia.

In this form of diabetes, the rate of -cell destruction is quite variable, being rapid in
some individuals (mainly infants and children) and slow in others (mainly adults). Some
patients, particularly children and adolescents, may present with ketoacidosis as the first
manifestation of the disease. Others have modest fasting hyperglycemia that can rapidly
change to severe hyperglycemia and/or ketoacidosis in the presence of infection or other
stress. Still others, particularly adults, may retain residual -cell function sufficient to
prevent ketoacidosis for many years; such individuals eventually become dependent on
insulin for survival and are at risk for ketoacidosis. At this latter stage of the disease,
there is little or no insulin secretion, as manifested by low or undetectable levels of
plasma C-peptide. Immunemediated diabetes commonly occurs in childhood and
adolescence, but it can occur at any age, even in the 8th and 9th decades of life.

Idiopathic diabetes. Some forms of type 1 diabetes have no known etiologies. Some of
these patients have permanent insulinopenia and are prone to ketoacidosis, but have no
evidence of autoimmunity. Although only a minority of patients with type 1 diabetes fall
into this category, of those who do, most are of African or Asian ancestry. Individuals
with this form of diabetes suffer from episodic ketoacidosis and exhibit varying degrees
of insulin deficiency between episodes. This form of diabetes is strongly inherited, lacks
immunological evidence for -cell autoimmunity, and is not HLA associated. An
absolute requirement for insulin replacement therapy in affected patients may come and

Type 2 diabetes       The pathogenesis of this type ranges from predominantly insulin
resistance with relative insulin deficiency to predominantly an insulin secretory defect
with insulin resistance. This form of diabetes, which accounts for 90–95% of those with
diabetes, previously referred to as non-insulindependent diabetes, type II diabetes, or
adult-onset diabetes, encompasses individuals who have insulin resistance and usually
have relative (rather than absolute) insulin deficiency. At least initially, and often
throughout their lifetime, these individuals do not need insulin treatment to survive.
There are probably many different causes of this form of diabetes. Although the specific
etiologies are not known, autoimmune destruction of -cells does not occur, and patients
do not have any of the other causes of diabetes listed above or below.

Most patients with this form of diabetes are obese, and obesity itself causes some degree
of insulin resistance. Patients who are not obese by traditional weight criteria may have
an increased percentage of body fat distributed predominantly in the abdominal region.
Ketoacidosis seldom occurs spontaneously in this type of diabetes; when seen, it usually
arises in association with the stress of another illness such as infection. This form of
diabetes frequently goes undiagnosed for many years because the hyperglycemia
develops gradually and at earlier stages is often not severe enough for the patient to
notice any of the classic symptoms of diabetes. Nevertheless, such patients are at
increased risk of developing macrovascular and microvascular complications. Whereas
patients with this form of diabetes may have insulin levels that appear normal or elevated,
the higher blood glucose levels in these diabetic patients would be expected to result in
even higher insulin values had their -cell function been normal. Thus, insulin secretion
is defective in these patients and insufficient to compensate for insulin resistance. Insulin
resistance may improve with weight reduction and/or pharmacological treatment of
hyperglycemia but is seldom restored to normal. The risk of developing this form of
diabetes increases with age, obesity, and lack of physical activity. It occurs more
frequently in women with prior GDM and in individuals with hypertension or
dyslipidemia, and its frequency varies in different racial/ ethnic subgroups. It is often
associated with a strong genetic predisposition, more so than is the autoimmune form of
type 1 diabetes. However, the genetics of this form of diabetes are complex and not
clearly defined.

Other specific types of diabetes
Genetic defects of the -cell. Several forms of diabetes are associated with monogenetic
defects in -cell function. These forms of diabetes are frequently characterized by onset
of hyperglycemia at an early age (generally before age 25 years). They are referred to as
maturityonset diabetes of the young (MODY) and are characterized by impaired insulin
secretion with minimal or no defects in insulin action. They are inherited in an autosomal
dominant pattern. Abnormalities at six genetic loci on different chromosomes have been
identified to date.The most common form is associated with mutations on chromosome
12 in a hepatic transcription factor referred to as hepatocyte nuclear factor (HNF)-1. A
second form is associated with mutations in the glucokinase gene on chromosome 7p and
results in a defective glucokinase molecule. Glucokinase converts glucose to
glucose-6-phosphate, the metabolism of which, in turn, stimulates insulin secretion by the
-cell. The less common forms result from mutations in other transcription factors,
including HNF-4,HNF-1, insulin promoter factor (IPF)-1, and NeuroD1. Point
mutations in mitochondrial DNA have been found to be associated with diabetes mellitus
and deafness. The most common mutation occurs at position 3243 in the tRNA leucine
gene, leading to an A-to-G transition. An identical lesion occurs in the MELAS syndrome
(mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like syndrome);
however, diabetes is not part of this syndrome, suggesting different phenotypic
expressions of this genetic lesion.

Genetic defects in insulin action.
There are unusual causes of diabetes that result from genetically determined
abnormalities of insulin action. The metabolic abnormalities associated with mutations of
the insulin receptor may range from hyperinsulinemia and modest hyperglycemia to
severe diabetes. Some individuals with these mutations may have acanthosis nigricans.
Women may be virilized and have enlarged, cystic ovaries. In the past, this syndrome
was termed type A insulin resistance. Leprechaunism and the Rabson-Mendenhall
syndrome are two pediatric syndromes that have mutations in the insulin receptor gene
with subsequent alterations in insulin receptor function and extreme insulin resistance.
The former has characteristic facial features and is usually fatal in infancy, while the
latter is associated with abnormalities of teeth and nails and pineal gland hyperplasia.
Alterations in the structure and function of the insulin receptor cannot be demonstrated in
patients with insulinresistant lipoatrophic diabetes. Therefore, it is assumed that the
lesion(s) must reside in the postreceptor signal transduction pathways.
Other specific types of diabetes, such as diseases of the exocrine pancreas,
endocrinopathies, drug- or chemical-induced diabetes,infections, uncommon forms of
immune-mediated diabetes)are listed in Table 1.

Gestational diabetes mellitus (GDM)
GDM is defined as any degree of glucose intolerance with onset or first recognition
during pregnancy. The definition applies regardless of whether insulin or only diet
modification is used for treatment or whether the condition persists after pregnancy. It
does not exclude the possibility that unrecognized glucose intolerance may have
antedated or begun concomitantly with the pregnancy. The prevalence may range from 1
to 14% of pregnancies, depending on the population studied. GDM represents nearly 90%
of all pregnancies complicated by diabetes. Deterioration of glucose tolerance occurs
normally during pregnancy, particularly in the 3rd trimester.

Diagnosis of GDM
Risk assessment for GDM should be undertaken at the first prenatal visit. Women with
clinical characteristics consistent with a high risk for GDM (those with marked obesity,
personal history of GDM, glycosuria, or a strong family history of diabetes) should
undergo glucose testing as soon as possible. High-risk women not found to have GDM at
the initial screening and average-risk women should be tested between 24 and 28 weeks
of gestation. Testing should follow one of two approaches:
● One-step approach: perform a diagnostic 100-g OGTT
● Two-step approach: perform an initial screening by measuring the plasma or serum
glucose concentration 1 h after a 50-g oral glucose load (glucose challenge test [GCT])
and perform a diagnostic 100-g OGTT on that subset of women exceeding the glucose
threshold value on the GCT. When the two step approach is used, a glucose threshold
value 140 mg/dl identifies 80% of women with GDM, and the yield is further increased
to 90% by using a cutoff of 130 mg/dl.
● Diagnostic criteria for the 100-g OGTT are as follows: 95 mg/dl fasting, 180 mg/dl
at 1 h, 155 mg/dl at 2 h, and140 mg/dl at 3 h. Two or more of the plasma glucose
values must be met or exceeded for a positive diagnosis.The test should be done in the
morning after an overnight fast of 8–14 h. The diagnosis can be made using a 75-g
glucose load, but that test is not as well
Table 2—Etiologic classification of       D. Endocrinopathies
diabetes mellitus                         1. Acromegaly
                                          2. Cushing’s syndrome
I. Type 1 diabetes (-cell destruction,   3. Glucagonoma
usually leading to absolute insulin       4. Pheochromocytoma
deficiency)                               5. Hyperthyroidism
A. Immune mediated                        6. Somatostatinoma
B. Idiopathic                             7. Aldosteronoma
                                          8. Others
II. Type 2 diabetes (may range from       E. Drug- or chemical-induced
predominantly insulin resistance with     1. Vacor
relative insulin deficiency to a          2. Pentamidine
predominantly secretory defect with       3. Nicotinic acid
insulin resistance)                       4. Glucocorticoids
                                          5. Thyroid hormone
III. Other specific types                 6. Diazoxide
                                          7. -adrenergic agonists
A. Genetic defects of -cell function     8. Thiazides
1. Chromosome 12, HNF-1 (MODY3)          9. Dilantin
2. Chromosome 7, glucokinase (MODY2)      10. -Interferon
3. Chromosome 20, HNF-4 (MODY1)          11. Others
4. Chromosome 13, insulin promoter        F. Infections
factor-1 (IPF-1; MODY4)                   1. Congenital rubella
5. Chromosome 17, HNF-1 (MODY5)          2. Cytomegalovirus
6. Chromosome 2, NeuroD1 (MODY6)          3. Others
7. Mitochondrial DNA                      G. Uncommon forms of
8. Others                                 immune-mediated diabetes
                                          1. ―Stiff-man‖ syndrome
B. Genetic defects in insulin action      2. Anti–insulin receptor antibodies
1. Type A insulin resistance              3. Others
2. Leprechaunism                          H. Other genetic syndromes sometimes
3. Rabson-Mendenhall syndrome             associated with diabetes
4. Lipoatrophic diabetes                  1. Down’s syndrome
5. Others                                 2. Klinefelter’s syndrome
                                          3. Turner’s syndrome
C. Diseases of the exocrine pancreas      4. Wolfram’s syndrome
1. Pancreatitis                           5. Friedreich’s ataxia
2. Trauma/pancreatectomy                  6. Huntington’s chorea
3. Neoplasia                              7. Laurence-Moon-Biedl syndrome
4. Cystic fibrosis                        8. Myotonic dystrophy
5. Hemochromatosis                        9. Porphyria
6. Fibrocalculous pancreatopathy          10. Prader-Willi syndrome
7. Others                                 11. Others

                                          IV. Gestational diabetes mellitus (GDM)

The DCCT (Diabetes Control and Complications Trial) and the UKPDS (U.K.
Prospective Diabetes Study) established that hyperglycemia is the initiating cause of the
diabetic tissue damage. This process is also modified by both genetic determinants of
individual susceptibility, and by independent accelerating factors such as hypertension.
Several major theories have been proposed to explain how hyperglycemia might lead to
the chronic complications Of DM.

Increased flux through the polyol pathway.
The polyol pathway focuses on the enzyme aldose reductase. Aldose reductase normally
has the function of reducing toxic aldehydes in the cell to inactive alcohols, but when the
glucose concentration in the cell becomes too high, aldose reductase also reduces that
glucose to sorbitol, which is later oxidized to fructose. In the process of reducing high
intracellular glucose to sorbitol, the aldose reductase consumes the cofactor NADPH,
which is also the essential cofactor for regenerating a critical intracellular antioxidant,
reduced glutathione. By reducing the amount of reduced glutathione, the polyol pathway
increases susceptibility to intracellular oxidative stress.

Intracellular production of AGE precursors.
The second discovery is the intracellular production of AGE precursors, which appear to
damage cells by three mechanisms. The first mechanism is the modification of
intracellular proteins including, most importantly, proteins involved in the regulation of
gene transcription. The second mechanism, shown on the left, is that these AGE
precursors can diffuse out of the cell and modify extracellular matrix molecules nearby,
which changes signaling between the matrix and the cell and causes cellular dysfunction.
The third mechanism, is that these AGE precursors diffuse out of the cell and modify
circulating proteins in the blood such as albumin. These modified circulating proteins can
then bind to AGE receptors and activate them, thereby causing the production of
inflammatory cytokines and growth factors, which in turn cause vascular pathology.

PKC activation.
The third mechanism was the PKC pathway. Hyperglycemia inside the cell increases the
synthesis of a molecule called diacylglycerol, which is a critical activating cofactor for the
classic isoforms of protein kinase-C, -ß, - , and - . When PKC is activated by
intracellular hyperglycemia, it has a variety of effects on gene expression. In each case,
the things that are good for normal function are decreased and the things that are bad are
increased. For example, the vasodilator producing endothelial nitric oxide (NO) synthase
(eNOS) is decreased, while the vasoconstrictor endothelin-1 is increased. Transforming
growth factor-ß and plasminogen activator inhibitor-1 are also increased.

Increased hexosamine pathway activity.
When glucose is high inside a cell, most of that glucose is metabolized through glycolysis,
going first to glucose-6 phosphate, then fructose-6 phosphate, and then on through the rest
of the glycolytic pathway. However, some of that fructose-6-phosphate gets diverted into
a signaling pathway in which an enzyme called GFAT (glutamine:fructose-6 phosphate
amidotransferase) converts the fructose-6 phosphate to glucosamine-6 phosphate and
finally to UDP (uridine diphosphate) N-acetyl glucosamine. What happens after that is the
N-acetyl glucosamine gets put onto serine and threonine residues of transcription factors,
just like the more familiar process of phosphorylation, and overmodification by this
glucosamine often results in pathologic changes in gene expression. For example,
increased modification of the transcription factor Sp1 results in increased expression of
transforming growth factor-ß1 and plasminogen activator inhibitor-1, both of which are
bad for diabetic blood vessels.

Hyperglycemia-induced mitochondrial superoxide production activates the four
damaging pathways by inhibiting GAPDH.
Figure 2 shows the scheme for how all of these data link together. This model is based on
a critical observation: diabetes in animals and patients, and hyperglycemia in cells, all
decrease the activity of the key glycolytic enzyme glyceraldehyde-3 phosphate
dehydrogenase (GAPDH). The level of all the glycolytic intermediates that are upstream
of GAPDH increase. Increased levels of the upstream glycolytic metabolite
glyceraldehyde-3-phosphate activates two of the four pathways. It activates the AGE
pathway because the major intracellular AGE precursor methylglyoxal is formed from
glyceraldehyde-3 phosphate. It also activates the classic PKC pathway, since the activator
of PKC, diacylglycerol, is also formed from glyceraldehyde-3 phosphate. Further
upstream, levels of the glycolytic metabolite fructose-6 phosphate increase, which
increases flux through the hexosamine pathway, where fructose-6 phosphate is converted
by the enzyme GFAT to UDP–N-acetylglucosamine (UDP-GlcNAc). Finally, inhibition
of GAPDH increases intracellular levels of the first glycolytic metabolite, glucose. This
increases flux through the polyol pathway, where the enzyme aldose reductase reduces it,
consuming NADPH in the process.

Thus, when intracellular hyperglycemia develops in target cells of diabetic complications,
it causes increased mitochondrial production of ROS. The ROS cause strand breaks in
nuclear DNA, which activate PARP. PARP then modifies GAPDH, thereby reducing its
activity. Finally, decreased GAPDH activity activates the polyol pathway, increases
intracellular AGE formation, activates PKC and subsequently NF B, and activates
hexosamine pathway flux.
Diabetic nephropathy
Diabetic nephropathy occurs in 20–40% of patients with diabetes and is the leading cause
of end-stage renal disease (ESRD).
Glomerular hyperfusion and renal hypertrophy occur in the first years after the onset of
DM and are reflected by increased glomerular filtration rate(GFR). During next 5 years
of DM , thickening of the glomerular basement membrane, glumerular hypertrophy, and
meseangial volume expansion occur as the GFR returns to normal. The earliest clinical
evidence of nephropathy is the appearance of low but abnormal levels (30 mg/day or 20
g/min) of albumin in the urine, referred to as microalbuminuria, and patients with
microalbuminuria are referred to as having incipient nephropathy. Microalbuminuria is
also a well-established marker of increased CVD risk. Without specific interventions,
80% of subjects with type 1 diabetes who develop sustained microalbuminuria have their
urinary albumin excretion increase at a rate of 10–20% per year to the stage of overt
nephropathy or clinical albuminuria(300 mg/24 h or200 g/min) over a period of 10–15
years, with hypertension also developing along the way. Once overt nephropathy occurs,
without specific interventions, the glomerular filtration rate (GFR) gradually falls over a
period of several years at a rate that is highly variable from individual to individual.
ESRD develops in 50% of type 1 diabetic individuals with overt nephropathy within 10
years and in 75% by 20 years. A higher proportion of individuals with type 2 diabetes are
found to have microalbuminuria and overt nephropathy shortly after the diagnosis of their
diabetes, because diabetes is actually present for many years before the diagnosis is made
and also because the presence of albuminuria may be less specific for the presence of
diabetic nephropathy, as shown by biopsy studies. Without specific interventions,
20–40% of type 2 diabetic patients with microalbuminuria progress to overt nephropathy,
but by 20 years after onset of overt nephropathy, only 20% will have progressed to ESRD.
Once the GFR begins to fall, the rates of fall in GFR are again highly variable from one
individual to another, but overall, they may not be substantially different between patients
with type 1 and patients with type 2 diabetes.

Diabetic retinopathy

Diabetic retinopathy is a highly specific vascular complication of both type 1 and type 2
diabetes. The prevalence of retinopathy is strongly related to the duration of diabetes.
Vision-threatening retinopathy is rare in type 1 diabetic patients in the first 3–5 years of
diabetes or before puberty. During the next two decades, nearly all type 1 diabetic
patients develop retinopathy. Up to 21% of patients with type 2 diabetes have retinopathy
at the time of first diagnosis of diabetes, and most develop some degree of retinopathy
over time. Diabetic retinopathy is estimated to be the most frequent cause of new cases of
blindness among adults aged 20–74 years.
Diabetic retinopathy progresses from mild nonproliferative abnormalities, to moderate
and severe nonproliferative diabetic retinopathy (NPDR). Nonproliferative diabetic
retinopathy is characterized by increased vascular microaneurysms, blot hemorrhages,
and cotton wool spots. Mild nonproliferative retinopathy to more extensive disease is
characterized by changes in venous vessel caliber, inttaretinal microvascular
abnormalities, and more numerous microaneurysms and hemorrhages. The
pathophysiologic mechanisms invoked in nonproliferative retinopathy include loss of
retinal pericytes, increased retinal vascular permeability, alterations in retinal blood flow,
and abnormal retinal microvasculature, all of which lead to retinal ischemia.
Proliferative diabetic retinopathy (PDR) is characterized by the growth of new blood
vessels on the retina and posterior surface of the vitreous. This newly formed blood
vessels rupture easily, leading to vitreous hemorrhage, fibrosis, and ultimately retinal
Macular edema, characterized by retinal thickening from leaky blood vessels, can
develop at all stages of retinopathy.
Intensive diabetes management with the goal of achieving near normoglycemia has been
shown in large prospective randomized studies to prevent and/or delay the onset of
diabetic retinopathy. In addition to hyperglycemia, high blood pressure is an established
risk factor for the development of macular edema and is associated with the presence of
proliferative diabetic retinopathy (PDR).

Diabetic neuropathy

Diabetic neuropathy can affect any part of the nervous system. This nerve disorder should
be suspected in all patients with type 2 diabetes and in patients who have had type 1
diabetes for more than five years. In some instances, patients with diabetic neuropathy
have few complaints, but their physical examination reveals mild to moderately severe
sensory loss. Idiopathic neuropathy has been found to precede the onset of type 2
diabetes or to occur as an early finding in the disease. The primary types of diabetic
neuropathy are sensorimotor and autonomic. A patient may have only one type of
neuropathy or might develop different combinations of neuropathies. Sensory
neuropathies can be classified as distal symmetric polyneuropathy, focal neuropathy (e.g.,
diabetic mononeuropathy), and diabetic amyotrophy. Motor neuropathies are identified
by the muscles that are involved. Autonomic neuropathies may be classified by the
system that is affected (e.g., endocrine, gastrointestinal, genitourinary).

In sensory nerve damage, the nerves with the longest axons usually are affected first,
resulting in a stocking-and-glove distribution. Small fiber damage affects sensation of
temperature, light touch, pinprick, and pain. Large fiber damage diminishes vibratory
sensation, position sense, muscle strength, sharp-dull discrimination, and two-point
discrimination. Polyradiculopathies and severe band-like abdominal pain also may occur.

Polyradiculopathy may be identified by electromyography or a sensory examination that
shows altered sensation along the course of the nerve trunk. Bilateral thigh pain or
weakness with atrophy of the iliopsoas, quadriceps, and adductor muscles also may be
present. Physical findings involving the L2, L3, and L4 nerve roots or an abnormal
electromyograph should alert the physician to the presence of polyradiculopathy.

Distal symmetric polyneuropathy, the most common form of diabetic neuropathy, affects
approximately 40 percent of patients who have had diabetes for 25 years or longer. Most
often, this neuropathy develops in the feet. The course is chronic and progressive; in rare
cases, however, the neuropathy resolves spontaneously in six to 12 months.

Distal symmetric polyneuropathy predisposes patients to variable pain, motor dysfunction,
nerve palsies, ulcers, burns, infections, gangrene, and Charcot's disease. Affected patients
also may develop neuropathic cachexia syndrome, which includes anorexia, depression,
and weight loss. When testing is performed in patients with distal symmetric
polyneuropathy and initial skin ulceration, almost 70 percent deny hypoesthesia, and
about 50 percent can sense a cotton wisp and pinprick.

Diabetic mononeuropathy has an acute onset and usually is asymmetric. Cranial,
truncal, and peripheral nerves are involved. The neuropathy generally
resolves spontaneously in three to 12 months, but in rare cases it may last
for years.Patients with diabetic mononeuropathy may develop visual changes
or muscle weakness involving cranial nerves III, IV, and VI, as well as Bell's
palsy. Cranial nerve III involvement results in ophthalmoplegia, ptosis, and
diplopia with sparing of pupillary function. The median, radial, and lateral
popliteal nerves are the most common sites of peripheral nerve
involvement.Occasionally, nerve palsies affect several unilateral nerves. When multiple
nerves are involved, the term "mononeuropathy multiplex‖ is used. Vasculitis should be
ruled out as a cause of the symptoms.

Diabetic amyotrophy, also known as femoral neuropathy or proximal motor neuropathy,
usually is bilateral and frequently is associated with weight loss. This condition causes
thigh muscle weakness, as well as variable pain and loss of the patellar reflex. Diabetic
amyotrophy tends to occur more often in older male patients with type 2 diabetes.
Thigh muscle atrophy is prominent, disabling, and usually limited to the iliopsoas,
quadriceps, and adductor muscles. Less often, the anterolateral calf muscles are involved.
Recovery usually is spontaneous in six to 12 months, but amyotrophy may recur.
Increasing circumferential thigh measurements may not indicate recovery because muscle
can be replaced by fatty tissue.

Diabetic autonomic neuropathy can develop in patients with type 1 or type
2 diabetes. Although autonomic neuropathy may occur at any stage of diabetes,
usually it develops in patients who have had the disease for 20 years or more
with poor glycemic control. Many investigators have considered autonomic
neuropathies to be irreversible. However, cardiac sympathetic
dysinnervation has been shown to regress with tight glycemic control.In
autonomic disease, the sympathetic, parasympathetic, and enteric nerves are
affected. Myelinated and unmyelinated nerve damage is found.

Cardiovascular neuropathy is a result of damage to vagal and sympathetic nerves.
Clinical findings may include exercise intolerance, persistent sinus tachycardia, no
variation in heart rate during activities, and bradycardia. Diabetic neuropathy also can
reduce appreciation of ischemic pain, which may delay appropriate medical therapy and
lead to death.

Vasomotor neuropathy frequently causes orthostatic hypotension by affecting the
splanchnic and peripheral vascular beds. Symptoms of syncope or dizziness often have
day-to-day variability and may be exacerbated by insulin therapy or the postprandial state,
in which there is splanchnic shunting of blood. The evaluation should include vital signs,
an ECG, and orthostatic blood pressure measurements.

In diabetic neuropathy, neuronal input to the peripheral vasculature is decreased or absent.
Resultant peripheral vasomotor instability can manifest as persistent excess peripheral
circulation (hyperemia) and peripheral edema. Loss of sympathetic tone in the blood
vessels results in maximal vasodilation, which can lead to arteriovenous shunting in the
soft tissue and bone. Increased blood flow through the bone causes calcium to wash from
the cortical stores. Defective bone homeostasis and bone demineralization may result.

The occurrence of peripheral vasomotor instability and peripheral sudomotor neuropathy
is termed "autosympathectomy.‖ The patient with autosympathectomy has peripheral
vasomotor reflexes similar to those in a nondiabetic patient after sympathectomy. The
mechanism by which the body senses and responds to changes in blood pressure by reflex
vasodilation or contraction of peripheral vessels is impaired. Autosympathectomy and
distal symmetric polyneuropathy are considered necessary for the development of
Charcot's disease (diabetic neuropathic arthropathy).

Sudomotor neuropathy may cause hyperhidrosis and heat intolerance in the upper torso or
anhidrosis in the lower extremities. Temperature elevation is rare, but sometimes occurs.
The skin of the extremities may feel pruritic and may display thinning, hair loss, dryness,
flaking, cracks, increased callus formation, and nail dystrophies. These skin changes
increase the risk of ulceration.

Gastrointestinal autonomic neuropathy may cause paresis anywhere in the digestive tract,
with damage to small myelinated and unmyelinated splanchnic nerves. Reduced
contraction amplitudes of the tubular esophagus may cause mild dysphagia. Motility
studies, such as scintigraphy after a radiolabeled meal, are helpful in the evaluation of
nausea, vomiting, early satiety, and delayed gastric emptying.

Diabetic diarrhea is caused by increased or uncoordinated transit time in the small
intestine, bacterial overgrowth, or increased intestinal secretion.13 Stool cultures and
flexible sigmoidoscopy may be helpful in excluding other causes of diarrhea, such as
parasitic infection, colon cancer or polyps, celiac sprue, and inflammatory bowel disease.

Decreased transit time in the large intestine may cause constipation or impacted stool.
Abdominal radiography or computed tomography may reveal megacolon or fecal
impaction. Neuropathic fecal incontinence also may occur in patients with
gastrointestinal autonomic neuropathy. A reduced threshold of conscious rectal sensation
is manifested by a decreased resting anal sphincter pressure.14

In patients with diabetic bladder dysfunction, inability to sense a full bladder and detrusor
muscle hypoactivity cause retention and incomplete voiding of urine. These conditions
can progress to overflow incontinence and urinary tract infections. Hyperglycemia alone
also can cause increased urine production and incontinence.

The evaluation of the patient with diabetes who has bladder dysfunction should begin
with a review of medications. Drugs that impair detrusor contractility and increase
urethral tone include calcium channel blockers, anticholinergics, alpha- and
beta-adrenergic agonists, narcotics, antidepressants, and antipsychotics. Further work-up
should include a patient's voiding record, postvoid residual testing, and urinalysis.
Cystometric and urodynamic studies confirm the diagnosis.

Erectile dysfunction can occur at an early age in men with diabetes.15 It develops in 35
percent of men with diabetes between 20 and 59 years of age and 65 percent of men with
diabetes 60 years or older.16 The primary cause is pelvic plexus neuropathy; a decrease
in nitric oxide, which is required to initiate an erection, contributes to the condition.

Routine screening is important because erectile dysfunction may occur before the
development of other autonomic signs. The evaluation of erectile dysfunction includes a
sexual history, a genital examination, a serum testosterone level, and prolactin and
thyrotropin levels.

In women, diabetic neuropathy may cause vaginal dryness, decreased perineal sensation,
dyspareunia, reduced libido, or anorgasmy. Routine screening should be performed
because sexual dysfunction may precede other autonomic signs. A detailed sexual history,
pelvic examination, and urinalysis help rule out other diagnoses.
Amputation and foot ulceration are the most common consequences of diabetic
neuropathy and major causes of morbidity and disability in people with diabetes. Early
recognition and management of independent risk factors can prevent or delay adverse
outcomes. The risk of ulcers or amputations is increased in people who have had diabetes
10 years, are male, have poor glucose control, or have cardiovascular, retinal, or renal
complications. The following foot-related risk conditions are associated with an increased
risk of amputation:
● Peripheral neuropathy with loss of protective sensation.
● Altered biomechanics (in the presence of neuropathy).
● Evidence of increased pressure (erythema, hemorrhage under a callus).
● Bony deformity.
● Peripheral vascular disease (decreased or absent pedal pulses).
● A history of ulcers or amputation.
● Severe nail pathology.

Diabetes is a chronic illness that requires continuing medical care and patient
self-management education o prevent acute complications and to reduce he risk of
long-term complications. Diabetes care is complex and requires that any issues, beyond
glycemic control, be addressed. A large body of evidence exists hat supports a range of
interventions to improve diabetes outcomes.
The management plan should be formulated as an individualized therapeutic alliance
among the patient and family, the physician, and other members of the health care team.
Any plan should recognize diabetes self-management education as an integral component
of care. In developing the plan, consideration should be given to the patient’s age, school
or work schedule and conditions, physical activity, eating patterns, social situation and
personality, cultural factors, and presence of complications of diabetes.


Self monitoring blood glucose (SMBG) is an integral component of diabetes therapy, it
allows patients to evaluate their individual response to therapy and assess whether
glycemic targets are being achieved. Results of SMBG can be useful in preventing
hypoglycemia and adjusting medications, MNT, and physical activity. The frequency and
timing of SMBG should be dictated by the particular needs and goals of the patients.
Daily SMBG is especially important for patients treated with insulin to monitor for and
prevent asymptomatic hypoglycemia. For most patients with type 1 diabetes and pregnant
women taking insulin, SMBG is recommended three or more times daily. The optimal
frequency and timing of SMBG for patients with type 2 diabetes is not known but should
be sufficient to facilitate reaching glucose goals. When adding to or modifying therapy,
type 1 and type 2 diabetic patients should test more often than usual.
By performing an A1C test, health providers can measure a patient’s average glycemia
over the preceding 2–3 months and, thus, assess treatment efficacy. A1C testing should
be performed routinely in all patients with diabetes, first to document the degree of
glycemic control at initial assessment and then as part of continuing care. Since the A1C
test reflects mean glycemia over the preceding 2–3 months, measurement approximately
every 3 months is required to determine whether a patient’s metabolic control has been
reached and maintained within the target range. Thus, regular performance of the A1C
test permits detection of departures from the target in a timely fashion. For any individual
patient, the frequency of A1C testing should be dependent on the clinical situation, the
treatment regimen used, and the judgmentof the clinician.

Glycemic control is best judged by the combination of the results of the patient’s SMBG
testing (as performed) and the current A1C result. The A1C should be used not only to
assess the patient’s control over the preceding 2–3 months but also as a check on the
accuracy of the meter (or the patient’s self-reported results) and the adequacy of the
SMBG testing schedule.

Medical nutrition therapy (MNT)
MNT is an integral and fundamental component of diabetes management and diabetes
self-management education. MNT involves a nutrition assessment to evaluate the
patient’s food intake, metabolic status, lifestyle and readiness to make changes, goal
setting, dietary instruction, and evaluation. To facilitate adherence, the plan should be
individualized and take into account cultural, lifestyle, and financial considerations.
The goal of MNT in the individual with type 1 DM is to coordinate and match the caloric
intake, both temporally and quantitatively, with the appropriate amount of insulin. MNT
must be flexible enough to allow for exercise, and insulin regimen must allow for
deviations in caloric intake. An important component of MNT in type 1 DM is to
minimize the weight gain often associated with intensive diabetes management.

Carbohydrate counting plays a central role in the dietary education of a patient with type
1diabetes. A patient on twice-daily regular and NPH insulin needs to have a fixed
carbohydrate intake(in terms of timing and quantity) so that the blood glucose rise
coincides with the predicted changes in plasma insulin. Many patients find such dietary
recommendations restrictive and prefer using insulin regimens that allow for more
flexibility in meal content and timing. The typical patient on a flexible insulin regimen
uses intermediate or long –acting insulin for basal coverage and ultra-short –acting or
short –acting insulin to cover the meals. Accurate assessment of carbohydrate content of
the meal then allows the patient to more precisely determine the dose of the premeal
insulin. Carbohydrate counting is even more important, since underestimation under these
circumstance can result in postprandial hypoglycemia. Fats and protein delay gastric
empting and can cause a mismatch in the postmeal glucose and insulin profiles. Simple
carbohydrates are not necessarily detrimental to blood glucose control, and patients can
occasionally include sucrose and concentrated sweets in a meal plan. Nocturnal
hypoglycemia remains an important problem, and a bedtime snack containing protein as
well as carbohydrate should be given 3 hours after evening insulin in order to provide
slow influx of carbohydrate from metabolized protein during most of the night.

The goals of MNT in type 2 DM are slightly different and address the greatly increased
prevalence of cardiovascular risk factors (hyperlipidemia, hypertention and obesity). It
emphasize modest caloric reduction, increased physical activity, and reduction of
hyperlipidemia and hypertention. Treatment requires a vigorous program to achieve
weight reduction. The total amount of calories prescribed must take into account the
patient’s ideal body weight, life style, and activity level. In obese type 2 patients, glucose
and lipid goals join weight loss as the focus for therapy. These patients are advised to
limit their carbohydrate intake by substituting noncholesterologenic monounsaturatedoils.
This maneuver is also indicated in type 1 patients on intensive insulin regimens in whom
near-normoglycemic control is less achievable on diets higher in carbohydrate content. In
these patients, the ratios of carbohydrate to fat will vary among individuals in relation to
their glycemic responses, insulin regimens, and exercise patterns.

Limit cholesterol to 300 mg daily and advise a daily protein intake of 10-20%total
calories. The saturated fat be no longer than 8-9%of total calories with a similar
proportion of polyunsatured fat and that the remainder of the caloric needs be made up of
an individualized ratios of monounsatured fat and that of carbohydrate containing 20-35g
dietary fiber.

Regular exercise has been shown to improve blood glucose control, reduce
cardiovascular risk factors, contribute to weight loss, and improve well-being.
Furthermore, regular exercise may prevent type 2 diabetes in high-risk individuals.

Before beginning a physical activity program, the patient with diabetes should have a
detailed medical evaluation with appropriate diagnostic studies. This examination should
screen for the presence of macro- and microvascular complications that may be worsened
by the physical activity program. Identification of areas of concern will allow the design
of an individualized physical activity plan that can minimize risk to the patient. All levels
of physical activity, including leisure activities, recreational sports, and competitive
professional performance, can be performed by people with diabetes who do not have
complications and have good glycemic control. The ability to adjust the therapeutic
regimen (insulin therapy and MNT) to allow safe participation is an important
management strategy.It recommends that individuals accumulate 30 min of moderate
physical activity on most days of the week.

For people with type 1 diabetes, the emphasis must be on adjusting the therapeutic
regimen to allow safe participation in all forms of physical activity consistent with an
individual’s desires and goals.

Antihyperglycemic agents
Orally administered antihyperglycemic agents (OHAs) can be used either alone or in
combination with other OHAs or insulin. OHAs are now available that target the
different pathophysiologic factors contributing to diabetes: -glucosidase inhibitors to
delay intestinal carbohydrate absorption, biguanides to target hepatic insulin resistance,
insulin secretagogues to increase pancreatic insulin secretion, insulin sensitizers or
thiazolidinediones to target adipocyte and muscle insulin resistance.

-Glucosidase inhibitors
Acarbose, Miglitol are -glucosidase inhibitors available in China. These drugs do not
target a specific pathophysiologic aspect of diabetes. This class of OHA competitively
inhibits enzymes in the small intestinal brush border that are responsible for the
breakdown of oligosaccharides and disaccharides into monosaccharides suitable for
absorption. It works primarily on -glucosidase, which is found predominantly in the
proximal half of the small intestine. The intestinal absorption of carbohydrates is
therefore delayed and shifted to more distal parts of the small intestine and colon. This
retards glucose entry into the systemic circulation and lowers postprandial glucose levels.
-Glucosidase inhibitors act locally at the intestinal brush border and are not absorbed.
They are excreted in feces.They are most useful in combination with other OHAs.
The main side effects of -glucosidase inhibitors are gastrointestinal. Specifically,
bloating, abdominal discomfort, diarrhea and flatulence occur in about 20% of patients.
Initiation of therapy at a low dose with slow titration upward may minimize these side
effects, and symptoms may diminish with continued use. Although hypoglycemia does
not occur when a drug in this class is used alone, in patients who are using it in
combination with another OHA or with insulin, hypoglycemia must be treated with
glucose itself (e.g., dextrose tablets) instead of complex carbohydrates, since absorption
of the latter is delayed. -Glucosidase inhibitors are contraindicated in patients with
irritable bowel syndrome or severe kidney or liver dysfunction. Inflammatory bowel
disease is a relative contraindication.

The mechanisms by which metformin exerts its antihyperglycemic effects are still not
entirely clear. Its major action in patients with diabetes is to decrease hepatic glucose
output, primarily by decreasing gluconeogenesis, but it may also, as a lesser effect,
increase glucose uptake by skeletal muscles. In 2001, Zhou and colleagues discovered
that metformin activates hepatic and muscle adenosine monophosphate-activated protein
kinase (AMPK), an enzyme normally activated by adenosine monophosphate, the
breakdown product of adenosine triphosphate and a cellular signal for increased energy
requirements). Activation of hepatic AMPK results in the phosphorylation and inhibition
of acetyl-coenzyme A carboxylase, which catalyzes the rate-limiting step of lipogenesis.
This block in fatty acid synthesis promotes fatty acid oxidation. In addition, activation of
hepatic AMPK decreases expression of sterol-regulatory-element-binding-protein-1
(SREBP-1), a transcription factor implicated in the pathogenesis of insulin resistance,
dyslipidemia and diabetes. Decreased SREBP-1 expression results in decreased gene
expression of lipogenic enzymes, which further contributes to decreased triglyceride
synthesis and hepatic steatosis. AMPK activation appears to be a critical step in the
metformin mediated reduction of hepatic glucose production and increase in skeletal
muscle glucose uptake. Thus, AMPK is a major regulator of lipid and glucose
metabolism and may be the key mediator of all the beneficial effects of metformin.
Metformin appears to have beneficial effects beyond glycemic control. It is associated
with weight loss, or at least with no weight gain. Improvements in lipid profile have also
been noted, with reductions in plasma levels of free fatty acids, triglycerides and
verylow- density lipoproteins in patients whose baseline levels are elevated. Increased
levels of plasminogen activator inhibitor-1 and C-reactive protein, both of which are
associated with increased cardiovascular risk, were also reduced with metformin. Thus
far, metformin is the only OHA to demonstrate significant cardiovascular benefit over
and above its glucose lowering effect in diabetes. Because of its ―insulin sensitizing‖
effect independent of insulin secretion, metformin has been used in type 1 diabetes to
lower insulin requirements.
Metformin is approved for use in diabetes either as monotherapy or in combination with
other OHAs, as well as with insulin. It is recommended as first-line therapy for
overweight patients with type 2 diabetes. It should be started at a low dose (500 mg once
daily) and titrated upward at 1–2-week intervals to a maximum dose of 1000 mg twice
daily. Metformin is covered by most provincial formularies and is relatively inexpensive .

Gastrointestinal side effects such as abdominal discomfort, anorexia, bloating and
diarrhea are observed in 10%–15% of patients, depending on the dose. The reason for
these effects is not known, but, like acarbose, metformin has been associated with
decreased intestinal glucose absorption. These side effects usually improve with
continued use and are minimal if started at a low dose (e.g., 250–500 mg/d) and slowly
titrated upward. Discontinuation of therapy because of side effects occurs in less than 4%
of patients. Since insulin secretion is not altered, hypoglycemia is not aside effect of
metformin when used as monotherapy. Similarly, unlike some of the other OHAs, weight
gain is not a side effect, and some patients experience weight loss. Although lactic
acidosis was frequently seen with the earlier biguanide phenformin, its association with
metformin has been rare. Monitoring of metformin safety revealed a very low risk of
lactic acidosis. The presence of another risk factor for lactic acidosis, such as acute renal
or liver failure, cardiogenic or septic shock, or hypoxemia, and the inability to correlate
lactate concentration or mortality with serum metformin concentrations in the metformin-
associated cases make it difficult to discern the contribution of metformin. The main
difference between metformin and phenformin is that metformin is rapidly excreted,
unchanged, by the kidneys, Thus,in the absence of impaired renal function, metformin is
less likely to accumulate. Metformin is contraindicated in patients with risk factors for
lactic acidosis or drug accumulation, in other words in those with moderate to severe
kidney, liver or cardiac dysfunction. Metformin may be used with extreme caution and in
reduced doses in patients with mild renal dysfunction, bearing in mind that renal function
may deteriorate rapidly in patients at risk for volume contraction.

Insulin secretagogues
Insulin secretagogues can be divided into 2 subclasses: sulfonylureas and
Sulfonylureas that are currently available are gliclazide, glimepiride, glyburide, and the
older agents chlorpropamide and tolbutamide. The last 2 are now rarely used.
Sulfonylureas bind to the sulfonylurea receptor on the surface of pancreatic cells. The
sulfonylurea receptor is intimately involved with subunits of an adenosine triphosphate-
sensitive potassium channel (kir6.2). The binding of a sulfonylurea to the sulfonylurea
receptor–kir6.2 complex results in closure of the potassium channels and inhibition of the
efflux of potassium ions from the resting  cell. This results in depolarization of the cell
membrane and, in turn, the opening of voltage-dependent calcium channels. The influx of
calcium causes microtubules to contract and the exocytosis of insulin from vesicles.
Sulfonylureas do not directly affect insulin sensitivity. The increase in insulin sensitivity
seen after treatment with these drugs is secondary to improved metabolic control.
Sulfonylureas are predominantly metabolized by the liver and cleared by the kidneys.
Several metabolites of glyburide are partially active, so that if clearance is impaired in
the kidney, the accumulating metabolites can have a significant hypoglycemic effect. In
contrast, gliclazide and glimepiride are metabolized by the liver to inactive metabolites.
In general, it is best to start with a low dose and titrate upward every 1–2 weeks to
achieve the desired glycemic control and avoid hypoglycemia, particularly in elderly
patients. Gliclazide is available in short- and long-acting formulations. The long-acting
modified release formulation can be administered once daily. Glimepiride is also
administered once daily. Glyburide may be administered once daily at 5 mg or less and
twice daily at higher doses.
The main side effects of sulfonylureas are hypoglycemia and weight gain. Given that
these drugs directly stimulate insulin secretion from pancreatic  cells irrespective of
plasma glucose levels, the risk of hypoglycemia is associated with all sulfonylureas. The
results of several large clinical trials indicate an average incidence of hypoglycemia of
1%–2% per year. Most episodes are mild and easily treated with glucose in the form of
fruit juice, sweetened beverages or glucose tablets. However, prolonged and severe
hypoglycemia can occur, especially in the setting of renal or hepatic impairment or in
frail, elderly patients. Gliclazide and glimepiride are less associated with hypoglycemia
than is glyburide. Since these medications are metabolized in the liver, sulfonylureas are
contraindicated in patients with moderate to severe liver dysfunction. The dose of
glyburide should either be markedly reduced or avoided altogether in elderly patients and
patients with moderate renal dysfunction. Dose adjustment is not required for gliclazide
or glimepiride in patients with moderate kidney dysfunction. However, there are
insufficient data to support their use in those with end-stage renal disease, in which case
insulin is the preferred option. The weight gain seen with sulfonylureas, which is
typically 2–5 kg, is likely related to the increase in plasma insulin levels. This may be
discouraging in a population that is already prone to obesity and often struggling to lose
weight. At the same time, metabolic control should not be compromised by withholding
treatment in an attempt to avoid weight gain. Side effects of first-generation agents
include skin rash, hyponatremia and alcohol-induced flushing.

This relatively new class of medications is currently represented by nateglinide and
repaglinide. Repaglinide is a benzoic acid derivative, and nateglinide is a phenylalanine
derivative. The mechanism of action of these drugs is similar to that of the sulfonylureas
(closure of the potassium–adenosine triphosphate channel, leading to calcium-dependent
insulin secretion). However, they bind to the sulfonylurea receptor at a different site and
with different kinetics than the sulfonylureas. Thus, the onset of action is faster and the
half-life is shorter, which results in a brief stimulation of insulin release. These
compounds are metabolized in the liver through the cytochrome p450 system into
inactive biliary products.
Given their rapid onset and short duration of action, non-sulfonylurea insulin
secretagogues are best taken just before meals. They may be taken 3 or even 4 times daily.
Postprandial hyperglycemia is well controlled. These medications are particularly useful
for patients who require meal-time flexibility, elderly patients and patients with impaired
renal function. For example, a dose may be omitted if a meal is skipped, and in the
elderly patient with unpredictable food intake, the dose may be given immediately after
the meal and titrated to the amount of food ingested. These medications can be used
either as monotherapy or in combination with other OHAs (but not sulfonylureas).
As with sulfonylureas, the main side effect of this class is hypoglycemia. However, the
risk of hypoglycemia is lower than that with sulfonylureas. This difference is due in part
to the shorter duration of action and in part to the glucose- dependent insulinotropic
effects of nateglinide. Similarly, the amount of weight gain appears to be less than that
seen with sulfonylureas, perhaps because of the limited duration of elevated insulin
secretion. The nonsulfonylurea insulin secretagogues are contraindicated in patients with
severe liver dysfunction, and the dose should be reduced in patients with severe kidney
dysfunction. Given the metabolism of repaglinide through the cytochrome p450 isozyme
CYP 3A4, glucose levels should be monitored carefully if the patient also receives a
strong inhibitor or inducer of the CYP 3A4 system. The combination of gemfibrozil, a
CYP 3A4 inhibitor, with repaglinide has been shown to dramatically increase the action
of repaglinide and result in prolonged hypoglycemia. This combination should therefore
be used cautiously or avoided. Nateglinide, on the other hand, is mostly metabolized via
the CYP 2C9 isozyme and requires CYP 3A4 metabolism to a lesser extent. No
interaction with gemfibrozil has been reported.

Insulin sensitizers (thiazolidinediones)
The 2 thiazolidinediones currently available are rosiglitazone and pioglitazone.
Thiazolidinediones function as ligands for the peroxisome proliferator-activated receptor
gamma (PPAR), which is most highly expressed in adipocytes. These nuclear receptors,
which are ligand-activated transcription factors, play an integral part in the regulation of
the expression of a variety of genes involved in carbohydrate and lipid metabolism.
Thiazolidinediones improve insulin sensitivity, particularly in the peripheral tissues. In
the adipocyte, differentiation is enhanced, lipolysis is reduced, and levels of circulating
adipo-cytokines or ―adipokines‖ are altered, namely a decrease in tumour necrosis
factor- and leptin and an increase in adiponectin. The ecruitment of a greater number
of smaller adipocytes, which is associated with improved lipogenesis and storage, results
in a reduction in circulating free fatty acids. All these effects — decreased tumour
necrosis factor- and free fatty acid levels and increased adiponectin levels — are
expected to enhance insulin sensitivity.
Preliminary data suggest that thiazolidinediones may have beneficial effects beyond that
of glycemic control. These include reduced urinary albumin excretion, increased levels of
high-density lipoprotein cholesterol and reduced triglyceride levels, lower blood pressure
and reduced levels of plasminogen activator inhibitor-1. Some studies have also
demonstrated improvement in surrogate markers of atherosclerosis, such as
intimal–medial thickness and neointimal proliferation after angioplasty. However, there
are no long-term microvascular or macrovascular clinical outcome data available yet on
the use of thiazolidinediones in patients with diabetes. Thiazolidinediones are approved
for use as monotherapy or in combination with metformin, sulfonylureas,
nonsulfonylurea insulin secretagogues or -glucosidase inhibitors (Box 1). Although
some effect can be seen in 2–3 weeks, it may take 6–12 weeks to observe the full blood
glucose lowering effect. Dose adjustments should be made accordingly. Patients should
be appropriately screened by history, physical examination and laboratory investigations
to rule out contraindications before therapy with thiazolidinediones is initiated. These
drugs are expensive, but some provincial formularies cover them under special
provisions .
The major side effects of rosiglitazone and pioglitazone are weight gain, edema, anemia,
pulmonary edema and congestive heart failure. The weight gain seen with
thiazolidinediones is similar to that observed with sulfonylureas. However, the
distribution of fat appears to be improved from a metabolic point of view — there is less
visceral fat and more peripheral fat. Peripheral edema can occur in about 3%–5% of
patients using thiazolidinedione as monotherapy and sometimes is severe enough that use
of the medication is stopped. The incidence of peripheral edema is increased when use of
the drug is combined with another glucose-lowering medication, particularly insulin.
Another adverse effect associated with thiazolidinedione use is anemia, which is
considered to represent hemodilution from sodium and water retention. The more serious
adverse events of pulmonary edema and congestive heart failure were infrequent in trials
of monotherapy (about 1%) but increased in combination therapy with insulin (about
2%–3%). In addition to congestive heart failure, the use of thiazolidinediones is
contraindicated in the presence of hepatic dysfunction. The fact that PPAR receptors
are present in other tissues, such as monocytes, macrophages, colonic epithelial cells and
pituitary cells, raises the possibility of long-term adverse or beneficial actions that are yet
to be determined.

In patients with mild to moderate hyperglycemia (hemoglobin A1c concentration < 9.0%),
lifestyle interventions should be implemented along with pharmacologic interventions as
needed. If the hyperglycemia is very mild, one could consider instituting lifestyle
interventions alone. If patients present with marked hyperglycemia (hemoglobin A1c
concentrations      9.0%), pharmacologic measures should be started immediately, along
with lifestyle modifications. Glycemic status should be reassessed frequently and
necessary changes made to achieve target hemoglobin A1c concentrations within 6–12
months. Metformin is recommended as the primary drug for overweight patients (body
mass index > 25 kg/m2), unless contraindicated.For nonoverweight patients, other classes
of OHAs can be used as primary therapy. The current guidelines recommend that the
addition of a different class of OHA be considered early to achieve glycemic targets. It
has been shown that combinations of submaximal doses of OHAs produce greater
reductions in hemoglobin A1c concentrations in a short period compared with maximum
dose monotherapy. As one would expect, the incidence of side effects(particularly
hypoglycemia) is higher with combination therapy than with monotherapy; however, the
difference is not significant. Dose adjustments or addition of other classes of medications,
or both, should occur in a timely fashion if targets are not achieved. A reasonable
duration after which a response in hemoglobin A1c concentrations is expected is 3
months for -glucosidase inhibitors, metformin and insulin secretagogues and 6 months
for thiazolidinediones.The choice of combinations requires knowledge of the mechanism
of action of the different classes. A common question in the management of diabetes is
when and how to institute insulin therapy. Although the details of insulin use are beyond
the scope of this review, the target hemoglobin A1c concentrations should remain the
primary indicator. Thus, if maximally tolerated doses of combination OHA therapy does
not achieve the desired glycemic targets, insulin should be started, either as monotherapy
or in combination with OHAs. The combination of insulin with the following agents has
been shown to have increased glucose-lowering effects:-glucosidase inhibitor,
metformin, sulfonylurea and thiazolidinedione. Sulfonylureas should not be combined
with preprandial insulin because of an increased risk of hypoglycemia. The decision to
use insulin alone or in combination with OHAs should be individualized and discussed
with the patient. There are no long-term clinical outcome data to support or detract from
using the combination approach. Regular follow-up and timely adjustments of
medications in all patients are mandatory since worsening glycemic control may be
expected, consistent with the natural history of diabetes. Therefore, choice and dose of
OHAs need to be reassessed on an ongoing basis.


Insulin is indicated for type 1diabetes as well as for those type 2 diabetics whose
hyperglycemia does not respond to diet and oral hypoglycemic drugs. In all instances of
insulin use, the insulin dosage must be individualized and balanced with medical nutrition
therapy and exercise.

Insulin is obtained from pork pancreas or is made chemically identical to human insulin
by recombinant DNA technology or chemical modification of pork insulin. with the
development of highly purified human insulin preparations, immunogenicity has been
markedly reduced, thereby decreasing the incidence of therapeutic complications such as
insulin allergy, immune insulin resistance, and localized lipoatrophy at the injection site.
Insulin analogs have been developed by modifying the amino acid sequence of the insulin

Insulin is available in rapid-, short-, intermediate-, and long-acting types that may be
injected separately or mixed in the same syringe. Rapid-acting insulin analogs (insulin
lispro and insulin aspart) are available, and other analogs are in development. Regular is a
short-acting insulin. Intermediate-acting insulins include lente and NPH. Ultralente and
insulin glargine are long-acting insulins. Insulin preparations with a predetermined
proportion of intermediate-acting insulin mixed with short- or rapid-acting insulin (e.g.,
70% NPH/30% regular, 50% NPH/50% regular, and 75% NPL/25% insulin lispro) are
available. Human insulins have a more rapid onset and shorter duration of activity than
pork insulins. Different types and species of insulin have different pharmacological
properties.(table) Insulin type and species, injection technique, insulin antibodies, site of
injection, and individual patient response differences can all affect the onset, degree, and
duration of insulin activity.
Vials of insulin not in use should be refrigerated. Extreme temperatures (<2 or >30°C)
and excess agitation should be avoided to prevent loss of potency, clumping, frosting, or
precipitation. Specific storage guidelines provided by the manufacturer should be
followed. Insulin in use may be kept at room temperature to limit local irritation at the
injection site, which may occur when cold insulin is used. Visual examination should
reveal rapid- and short-acting insulins as well as insulin glargine to be clear and all other
insulin types to be uniformly cloudy. Conventional insulin administration involves
subcutaneous injection with syringes marked in insulin units. Several pen-like devices
and insulin-containing cartridges are available that deliver insulin subcutaneously through
a needle. In many patients (e.g., especially those who are neurologically impaired and
those using multiple daily injection regimens), these devices have been demonstrated to
improve accuracy of insulin administration and/or adherence. Injections are made into the
subcutaneous tissue. Insulin may be injected into the subcutaneous tissue of the upper
arm and the anterior and lateral aspects of the thigh, buttocks, and abdomen (with the
exception of a circle with a 2-inch radius around the navel). Intramuscular injection is not
recommended for routine injections. Rotation of the injection site is important to prevent
lipohypertrophy or lipoatrophy. Rotating within one area is recommended (e.g., rotating
injections systematically within the abdomen) rather than rotating to a different area with
each injection. This practice may decrease variability in absorption from day to day. Site
selection should take into consideration the variable absorption between sites. The
abdomen has the fastest rate of absorption, followed by the arms, thighs, and buttocks.
Exercise increases the rate of absorption from injection sites, probably by increasing
blood flow to the skin and perhaps also by local actions. Areas of lipohypertrophy usually
show slower absorption. The rate of absorption also differs between subcutaneous and
intramuscular sites. The latter is faster and, although not recommended for routine use,
can be given under other circumstances (e.g., diabetic ketoacidosis or dehydration).

Approximate Pharmacokinetic Parameters of Currently Available Insulin Preparations
Following Subcutaneous Injection of an Average Patient Dose

Type of         Onset of Peak of Duration
insulin         action action of action         Common pitfalls

Insulin lispro 5 to 15 1 to 2      4 to 5       Hypoglycemia occurs if the lag time is
(Humalog)      minutes hours       hours        too long or the patient exercises within
                                                one hour of administration; with high-fat
                                                meals, the dose should be adjusted
Regular     30 to 60 2 to 4        6 to 8       Lag time is not used appropriately; the
insulin     minutes hours          hours        insulin should be given 20 to 30 minutes
(Humulin R)                                     before the patient eats.
NPH insulin 1 to 3   5 to 7        13 to 18     In many patients, breakfast injection does
(Humulin N) hours        hours    hours       not last until the evening meal;
                                              administration with the evening meal
                                              does not meet insulin needs on
Lente insulin 1 to 3     4 to 8   13 to 20    Zinc suspension binds with regular
(Humulin L) hours        hours    hours       insulin, which loses its effect if it is left in
                                              the syringe for more than a few minutes.
Ultralente  2 to 4       8 to 14 20 to 24     Same as for lente insulin; in addition,
insulin     hours        hours hours          peak of action is erratic in some patients.
(Humulin U)

*--Estimated cost to the pharmacist based on average wholesale prices (rounded to the
nearest dollar) in Red book. Montvale, N.J.: Medical Economics Data, 1999. Cost to the
patient will be greater, depending on prescription filling fee.
Insulin dose

Most patients with C-peptide negative type 1 diabetes require an insulin dosage of 0.5 to
1.0 unit per kg per day. Athletes and patients near ideal body weight generally require
less insulin than sedentary or obese patients. In addition, patients with newly diagnosed
type 1 diabetes generally have smaller initial insulin requirements because of continued
endogenous insulin secretion. In children and adults, insulin requirements immediately
after diagnosis are usually in the range of 0.2 to 0.6 unit per kg per day. In these patients,
glucose levels generally are less labile than they become when endogenous insulin
production ceases completely. During this "honeymoon period," or "remission," it may be
tempting to discontinue insulin administration altogether. However, discontinuation is not
recommended because data suggest that the insulin may be altering the immune system to
retard beta-cell destruction.
The basal component restrains hepatic glucose production, keeping it in equilibrium with
tissues that are obligate glucose consumers (such as brain tissue). Mealtime insulin
stimulates peripheral glucose uptake while inhibiting hepatic glucose output. the basal
and mealtime components must be identified. Basal insulin may be provided as (1)
bedtime intermediate-acting insulin with or without morning intermediate-acting insulin,
(2) ultralente insulin, usually administered twice daily, or (3) insulin pump therapy.
Dosing can be determined only by assessing the blood glucose level after the insulin
administered at mealtime has dissipated and food has been digested.

Twice-daily insulin injections may be effective for at least a short period in patients with
newly diagnosed type 1 diabetes who are still producing a significant amount of insulin ,
the peak of action for NPH or lente insulin creates several problems. The morning
administration of a large dose of intermediate-acting insulin with regular insulin results in
hyperinsulinemia at midday. If lunch is delayed even a short time in patients who
maintain reasonable glycemia after breakfast, hypoglycemia ensues. To avoid this
problem, many patients require a midmorning snack, even when lunch is not delayed. For
patients on this regimen, a lack of hypoglycemia, even after a long delay to the midday
meal, strongly suggests extremely high morning glucose levels. In many patients,
especially those who are young and thin, the morning insulin tends to dissipate by late
afternoon, resulting in high glucose levels before the evening meal. This particular issue
was not as great a problem with bovine and porcine insulins, because they had longer
durations of action than the human insulins used today.

Perhaps an even greater problem is maintenance of nocturnal glycemic control when an
intermediate-acting insulin is injected with the evening meal .With the peaking of insulin
occurring in the middle of the night, patients are predisposed to nocturnal hypoglycemia
at a time when insulin requirements are at their lowest.(Somogyi phenomena) .
Furthermore, when NPH or lente insulin is administered at the evening meal, the insulin
often does not sustain its effect throughout the night, and fasting hyperglycemia occurs. It
is important to determine if the blood glucose level is maintained within the target range
after breakfast. For example, if the glucose level before the midday meal is consistently
elevated and the glucose level two hours after the meal is usually within the target range,
the basal component in the morning may be too low. If the blood glucose level before the
midday meal is above the target range and the glucose level two hours after the meal is
also usually high, the mealtime insulin component is probably insufficient, or perhaps the
basal and mealtime insulins need adjustment to a larger dose.

One popular solution to the problem of nocturnal insulin replacement is to delay
administration of the intermediate-acting insulin until bedtime.With this approach, serum
insulin levels before breakfast are higher (better matching insulin requirements), and
nocturnal hypoglycemia should be less of a problem. When mealtime insulin is only
administered twice (at morning and evening meals), mealtime flexibility is not
significantly improved.
When regular insulin is used at mealtimes, some physicians prefer using bedtime
intermediate-acting insulin as the only basal insulin. Because of regular insulin's
relatively long duration of action, this approach may be effective in many patients. An
injection of regular insulin is also given before the midday meal. This increases flexibility
in that the timing of the midday meal may be more varied, and a specific dose of insulin
may be administered based on the blood glucose level, anticipated food consumption and
planned exercise. Other physicians prefer administration of a small dose of
intermediate-acting insulin in the morning, a larger dose at bedtime and doses of insulin
at mealtimes when needed. Many physicians believe that this results in "smoother"
glycemia during the day. Perhaps more importantly, if insulin lispro is used as the
mealtime insulin, a minimum of two injections of intermediate-acting insulin is required.
Ultralente Insulin as the Basal Insulin. Recently, ultralente insulin programs have become
more popular . It is easiest to start ultralente insulin at approximately 50 percent of the
total daily dosage, with one half of the dosage given with breakfast and the rest with the
evening meal.

Persistent fasting hyperglycemia may be treated by increasing the dose of ultralente
insulin that is given at the evening meal. However, this approach may not be effective in
some patients, because nocturnal hypoglycemia may occur without any improvement in
fasting hyperglycemia as a result of the dawn phenomenon.

The carbohydrate content of a meal is quantitatively more important than the protein or
fat content in determining insulin requirements. Therefore, a considerable degree of
attention has been given to carbohydrate counting as a more precise way of determining
mealtime insulin doses.With this method, patients are taught how to count the grams of
carbohydrates they anticipate eating at a meal, and the dose of regular insulin or insulin
lispro to be taken before the meal is then calculated based on the ratio of insulin to
carbohydrate content. For example, 1 unit of insulin lispro may be appropriate for every
15 g of carbohydrate in a meal. This ratio needs to be individualized, and it may even
vary for the same patient at different times of the day.Although some patients can
manage carbohydrate counting and insulin dose calculation, many patients find these
tasks difficult. Others prefer to employ a carbohydrate goal (e.g., bread exchanges) and
then use an insulin-to-carbohydrate ratio for additional (or less) carbohydrate. Regular
insulin or insulin lispro may then be added (or subtracted) appropriately.

Continuous subcutaneous insulin infusion,CSII, is alternative way to provide intensive
insulin therapy. CSII may provide great lifestyle flexibility, particularly with regard to
meal schedules and travel but may be too demanding for some individuals. CSII can help
improve metabolic control during pregnancy.

Diabetic ketoacidosis (DKA) and hyperglycemic state (HHS)
Ketoacidosis and hyperosmolar hyperglycemia are the two most serious acute metabolic
complications of diabetes, even if managed properly. These disorders can occur in both
type 1 and type 2 diabetes. The mortality rate in patients with diabetic ketoacidosis (DKA)
is <5% in experienced centers, whereas the mortality rate of patients with hyperosmolar
hyperglycemic state (HHS) still remains high at 15%. The prognosis of both conditions
is substantially worsened at the extremes of age and in the presence of coma and


Although the pathogenesis of DKA is better understood than that of HHS, the basic
underlying mechanism for both disorders is a reduction in the net effective action of
circulating insulin coupled with a concomitant elevation of counterregulatory hormones,
such as glucagon, catecholamines, cortisol, and growth hormone. These hormonal
alterations in DKA and HHS lead to increased hepatic and renal glucose production and
impaired glucose utilization in peripheral tissues, which result in hyperglycemia and
parallel changes in osmolality of the extracellular space. The combination of insulin
deficiency and increased counterregulatory hormones in DKA also leads to the release of
free fatty acids into the circulation from adipose tissue (lipolysis) and to unrestrained
hepatic fatty acid oxidation to ketone bodies (ß-hydroxybutyrate [ß-OHB] and
acetoacetate), with resulting ketonemia and metabolic acidosis. On the other hand, HHS
may be caused by plasma insulin concentrations that are inadequate to facilitate glucose
utilization by insulin-sensitive tissues but adequate (as determined by residual C-peptide)
to prevent lipolysis and subsequent ketogenesis, although the evidence for this is weak.
Both DKA and HHS are associated with glycosuria, leading to osmotic diuresis, with loss
of water, sodium, potassium, and other electrolytes. DKA and HHS differ in magnitude of
dehydration and degree of ketosis (and acidosis).

precipitating factor
 The most common precipitating factor in the development of DKA or HHS is infection.
Other precipitating factors include cerebrovascular accident, alcohol abuse, pancreatitis,
myocardial infarction, trauma, and drugs. In addition, new-onset type 1 diabetes or
discontinuation of or inadequate insulin in established type 1 diabetes commonly leads to
the development of DKA. Elderly individuals with new-onset diabetes (particularly
residents of chronic care facilities) or individuals with known diabetes who become
hyperglycemic and are unaware of it or are unable to take fluids when necessary are at
risk for HHS.

Drugs that affect carbohydrate metabolism, such as corticosteroids, thiazides, and
sympathomimetic agents (e.g., dobutamine and terbutaline), may precipitate the
development of HHS or DKA. In young patients with type 1 diabetes, psychological
problems complicated by eating disorders may be a contributing factor in 20% of
recurrent ketoacidosis. Factors that may lead to insulin omission in younger patients
include fear of weight gain with improved metabolic control, fear of hypoglycemia,
rebellion from authority, and stress of chronic disease
History and physical examination
The process of HHS usually evolves over several days to weeks, whereas the evolution of
the acute DKA episode in type 1 diabetes or even in type 2 diabetes tends to be much
shorter. Although the symptoms of poorly controlled diabetes may be present for several
days, the metabolic alterations typical of ketoacidosis usually evolve within a short time
frame (typically <24 h). Occasionally, the entire symptomatic presentation may evolve or
develop more acutely, and the patient may present in DKA with no prior clues or
symptoms. For both DKA and HHS, the classical clinical picture includes a history of
polyuria, polydipsia, polyphagia, weight loss, vomiting, abdominal pain (only in DKA),
dehydration, weakness, clouding of sensoria, and finally coma. Physical findings may
include poor skin turgor, Kussmaul respirations (in DKA), tachycardia, hypotension,
alteration in mental status, shock, and ultimately coma (more frequent in HHS). Up to
25% of DKA patients have emesis, which may be coffee-ground in appearance and guaiac
positive. Endoscopy has related this finding to the presence of hemorrhagic gastritis.
Mental status can vary from full alertness to profound lethargy or coma, with the latter
more frequent in HHS. Although infection is a common precipitating factor for both
DKA and HHS, patients can be normothermic or even hypothermic primarily because of
peripheral vasodilation. Hypothermia, if present, is a poor prognostic sign. Caution needs
to be taken with patients who complain of abdominal pain on presentation, because the
symptoms could be either a result or an indication of a precipitating cause (particularly in
younger patients) of DKA. Further evaluation is necessary if this complaint does not
resolve with resolution of dehydration and metabolic acidosis.

Laboratory findings
The initial laboratory evaluation of patients with suspected DKA or HHS should include
determination of plasma glucose, blood urea nitrogen/creatinine, serum ketones,
electrolytes (with calculated anion gap), osmolality, urinalysis, urine ketones by dipstick,
as well as initial arterial blood gases, complete blood count with differential, and
electrocardiogram. Bacterial cultures of urine, blood, and throat, etc., should be obtained
and appropriate antibiotics given if infection is suspected. HbA1c may be useful in
determining whether this acute episode is the culmination of an evolutionary process in
previously undiagnosed or poorly controlled diabetes or a truly acute episode in an
otherwise well-controlled patient. A chest X-ray should also be obtained if indicated.

The majority of patients with hyperglycemic emergencies present with leukocytosis
proportional to blood ketone body concentration. Serum sodium concentration is usually
decreased because of the osmotic flux of water from the intracellular to the extracellular
space in the presence of hyperglycemia, and less commonly, serum sodium concentration
may be falsely lowered by severe hypertriglyceridemia. Serum potassium concentration
may be elevated because of an extracellular shift of potassium caused by insulin
deficiency, hypertonicity, and acidemia. Patients with low-normal or low serum
potassium concentration on admission have severe total-body potassium deficiency and
require very careful cardiac monitoring and more vigorous potassium replacement,
because treatment lowers potassium further and can provoke cardiac dysrhythmia. The
occurrence of stupor or coma in diabetic patients in the absence of definitive elevation of
effective osmolality ( 320 mOsm/kg) demands immediate consideration of other causes
of mental status change. Effective osmolality may be calculated by the following formula:
2[measured Na (mEq/l)] + glucose (mg/dl)/18. Amylase levels are elevated in the
majority of patients with DKA, but this may be due to nonpancreatic sources, such as the
parotid gland. A serum lipase determination may be beneficial in the differential
diagnosis of pancreatitis. However, lipase could also be elevated in DKA. Abdominal
pain and elevation of serum amylase and liver enzymes are noted more commonly in
DKA than in HHS.

Differential diagnosis
Not all patients with ketoacidosis have DKA. Starvation ketosis and alcoholic
ketoacidosis (AKA) are distinguished by clinical history and by plasma glucose
concentrations that range from mildly elevated (rarely >250 mg/dl) to hypoglycemia. In
addition, although AKA can result in profound acidosis, the serum bicarbonate
concentration in starvation ketosis is usually not lower than 18 mEq/l. DKA must also be
distinguished from other causes of high-anion gap metabolic acidosis, including lactic
acidosis, ingestion of drugs such as salicylate, methanol, ethylene glycol, and paraldehyde,
and chronic renal failure (which is more typically hyperchloremic acidosis rather than
high-anion gap acidosis). Clinical history of previous drug intoxications or metformin use
should be sought. Measurement of blood lactate, serum salicylate, and blood methanol
level can be helpful in these situations. Ethylene glycol (antifreeze) is suggested by the
presence of calcium oxalate and hippurate crystals in the urine.

Paraldehyde ingestion is indicated by its characteristic strong odor on the breath. Because
these intoxicants are low-molecular weight organic compounds, they can produce an
osmolar gap in addition to the anion gap acidosis.


Successful treatment of DKA and HHS requires correction of dehydration, hyperglycemia,
and electrolyte imbalances; identification of comorbid precipitating events; and above all,
frequent patient monitoring.
Fluid therapy
Initial fluid therapy is directed toward expansion of the intravascular and extravascular
volume and restoration of renal perfusion. In the absence of cardiac compromise, isotonic
saline (0.9% NaCl) is infused at a rate of 15–20 ml · kg-1 body wt · h-1 or greater during
the 1st hour ( 1–1.5 l in the average adult). Subsequent choice for fluid replacement
depends on the state of hydration, serum electrolyte levels, and urinary output. In general,
0.45% NaCl infused at 4–14 ml · kg-1 · h-1 is appropriate if the corrected serum sodium is
normal or elevated; 0.9% NaCl at a similar rate is appropriate if corrected serum sodium
is low. Once renal function is assured, the infusion should include 20–30 mEq/l potassium
(2/3 KCl and 1/3 KPO4) until the patient is stable and can tolerate oral supplementation.
Successful progress with fluid replacement is judged by hemodynamic monitoring
(improvement in blood pressure), measurement of fluid input/output, and clinical
examination. Fluid replacement should correct estimated deficits within the first 24 h.
The induced change in serum osmolality should not exceed 3 mOsm · kg-1 H2O · h-1. In
patients with renal or cardiac compromise, monitoring of serum osmolality and frequent
assessment of cardiac, renal, and mental status must be performed during fluid
resuscitation to avoid iatrogenic fluid overload.

Insulin therapy
Unless the episode of DKA is mild, regular insulin by continuous intravenous infusion is
the treatment of choice. In adult patients, once hypokalemia (K+ <3.3 mEq/l) is excluded,
an intravenous bolus of regular insulin at 0.15 units/kg body wt, followed by a continuous
infusion of regular insulin at a dose of 0.1 unit · kg-1 · h-1 (5–7 units/h in adults), should
be administered. An initial insulin bolus is not recommended in pediatric patients; a
continuous insulin infusion of regular insulin at a dose of 0.1 unit · kg-1 · h-1 may be
started in these patients. This low dose of insulin usually decreases plasma glucose
concentration at a rate of 50–75 mg · dl-1 · h-1, similar to a higher-dose insulin regimen. If
plasma glucose does not fall by 50 mg/dl from the initial value in the 1st hour, check
hydration status; if acceptable, the insulin infusion may be doubled every hour until a
steady glucose decline between 50 and 75 mg/h is achieved.

When the plasma glucose reaches 250 mg/dl in DKA or 300 mg/dl in HHS, it may be
possible to decrease the insulin infusion rate to 0.05–0.1 unit · kg-1 · h-1 (3–6 units/h), and
dextrose (5–10%) may be added to the intravenous fluids. Thereafter, the rate of insulin
administration or the concentration of dextrose may need to be adjusted to maintain the
above glucose values until acidosis in DKA or mental obtundation and hyperosmolarity
in HHS are resolved.

Ketonemia typically takes longer to clear than hyperglycemia. Direct measurement of
ß-OHB in the blood is the preferred method for monitoring DKA. The nitroprusside
method only measures acetoacetic acid and acetone. However, ß-OHB, the strongest and
most prevalent acid in DKA, is not measured by the nitroprusside method. During therapy,
ß-OHB is converted to acetoacetic acid, which may lead the clinician to believe that
ketosis has worsened. Therefore, assessments of urinary or serum ketone levels by the
nitroprusside method should not be used as an indicator of response to therapy. During
therapy for DKA or HHS, blood should be drawn every 2–4 h for determination of serum
electrolytes, glucose, blood urea nitrogen, creatinine, osmolality, and venous pH (for
DKA). Generally, repeat arterial blood gases are unnecessary; venous pH (which is
usually 0.03 units lower than arterial pH) and anion gap can be followed to monitor
resolution of acidosis. With mild DKA, regular insulin given either subcutaneously or
intramuscularly every hour is as effective as intravenous administration in lowering blood
glucose and ketone bodies. Patients with mild DKA should first receive a "priming" dose
of regular insulin of 0.4–0.6 units/kg body wt, half as an intravenous bolus and half as a
subcutaneous or intramuscular injection. Thereafter, 0.1 unit · kg-1 · h-1 of regular insulin
should be given subcutaneously or intramuscularly.

Criteria for resolution of DKA includes a glucose <200 mg/dl, serum bicarbonate 18
mEq/l, and a venous pH of >7.3. Once DKA is resolved, if the patient is NPO, continue
intravenous insulin and fluid replacement and supplement with subcutaneous regular
insulin as needed every 4 h. When the patient is able to eat, a multiple-dose schedule
should be started that uses a combination of short- or rapid-acting and intermediate- or
long-acting insulin as needed to control plasma glucose. Continue intravenous insulin
infusion for 1–2 h after the split-mixed regimen is begun to ensure adequate plasma
insulin levels. An abrupt discontinuation of intravenous insulin coupled with a delayed
onset of a subcutaneous insulin regimen may lead to worsened control; therefore, some
overlap should occur in intravenous insulin therapy and initiation of the subcutaneous
insulin regimen. Patients with known diabetes may be given insulin at the dose they were
receiving before the onset of DKA or HHS and further adjusted as needed for control. In
patients with newly diagnosed diabetes, the initial total insulin dose should be 0.5–1.0
units · kg -1 · day-1, divided into at least two doses in a regimen including short- and
long-acting insulin until an optimal dose is established. Finally, some type 2 diabetes
patients may be discharged on oral antihyperglycemic agents and dietary therapy.

Despite total-body potassium depletion, mild to moderate hyperkalemia is not uncommon
in patients with hyperglycemic crises. Insulin therapy, correction of acidosis, and volume
expansion decrease serum potassium concentration. To prevent hypokalemia, potassium
replacement is initiated after serum levels fall below 5.5 mEq/l, assuming the presence of
adequate urine output. Rarely, DKA patients may present with significant hypokalemia.
In such cases, potassium replacement should begin with fluid therapy, and insulin
treatment should be delayed until potassium concentration is restored to >3.3 mEq/l to
avoid arrhythmias or cardiac arrest and respiratory muscle weakness. Insulin, as well as
bicarbonate therapy, lowers serum potassium; therefore, potassium supplementation
should be maintained in intravenous fluid as described above and carefully monitored.

Bicarbonate use in DKA remains controversial. At a pH >7.0, reestablishing insulin
activity blocks lipolysis and resolves ketoacidosis without any added bicarbonate. Given
that severe acidosis may lead to a myriad of adverse vascular effects, it seems prudent that
for adult patients with a pH <6.9, 100 mmol sodium bicarbonate be added to 400 ml
sterile water and given at a rate of 200 ml/h. In patients with a pH of 6.9–7.0, 50 mmol
sodium bicarbonate is diluted in 200 ml sterile water and infused at a rate of 200 ml/h. No
bicarbonate is necessary if pH is >7.0. Venous pH should be assessed every 2 h until the
pH rises to 7.0, and treatment should be repeated every 2 h if necessary. If the pH remains
<7.0 after the initial hour of hydration, it seems prudent to administer 1–2 mEq/kg sodium
bicarbonate over the course of 1 h. This sodium bicarbonate can be added to NaCl, with
any required potassium, to produce a solution that does not exceed 155 mEq/l sodium.


Many cases of DKA and HHS can be prevented by better access to medical care, proper
education, and effective communication with a health care provider during an intercurrent
illness. Sick-day management should be reviewed periodically with all patients. It should
include specific information on 1) when to contact the health care provider, 2) blood
glucose goals and the use of supplemental short-acting insulin during illness, 3) means to
suppress fever and treat infection, and 4) initiation of an easily digestible liquid diet
containing carbohydrates and salt. Most importantly, the patient should be advised to
never discontinue insulin and to seek professional advice early in the course of the illness.
Successful sick-day management depends on involvement by the patient and/or a family
member. The patient/family member must be able to accurately measure and record blood
glucose, urine or blood ketone determination when blood glucose is >300 mg/dl, insulin
administered, temperature, respiratory and pulse rate, and body weight and must be able
to communicate this to a health care professional. Adequate supervision and help from
staff or family may prevent many of the admissions for HHS due to dehydration among
elderly individuals who are unable to recognize or treat this evolving condition. Better
education of care givers as well as patients regarding signs and symptoms of new-onset
diabetes; conditions, procedures, and medications that worsen diabetes control; and the
use of glucose monitoring could potentially decrease the incidence and severity of HHS.