DIABETES MELLITUS (DM)

Etiology and Prevalence

DM comprises a group of metabolic disorders that share the common feature of
hyperglycemia. Type 1 DM is characterized by insulin deficiency and a tendency to develop
ketosis, whereas type 2 DM is a heterogeneous group of disorders characterized by variable
degrees of insulin resistance, impaired insulin secretion, and excessive hepatic glucose
production. Other types include DM caused by genetic defects (maturity-onset diabetes of the
young [MODY]), exocrine pancreas diseases (chronic pancreatitis, cystic fibrosis,
hemochromatosis), endocrinopathies (acromegaly, Cushing’s syndrome, glucagonoma,
pheochromocytoma, hyperthyroidism), drugs (nicotinic acid, glucocorticoids, thiazides, protease
inhibitors), and pregnancy (gestational DM). Phenotype of these monogenetic and secondary
types resembles type 2 DM; its severity depends on the degree of beta cell dysfunction and
insulin resistance. Type 1 DM or juvenile-onset diabetes results from autoimmune destruction of
pancreatic beta cells. Prevalence of DM is increasing rapidly; type 2 DM frequency is rising in
parallel with the epidemic of obesity. DM is the 5th leading cause of death worldwide.

Diagnosis
Criteria for the diagnosis of DM include one of the following:
 Fasting plasma glucose ≥7.0 mmol/L (≥126 mg/dL)
 Symptoms of diabetes plus a random blood glucose concentration ≥11.1 mmol/L (≥200
mg/dL)
 2-h plasma glucose ≥11.1 mmol/L (≥200 mg/dL) during a 75-g oral glucose tolerance
test.
 Hemoglobin A1c >6.5%
These should be confirmed by repeat testing on a different day, unless unequivocal
hyperglycemia is present.
Two intermediate categories also have been designated:
 Impaired fasting glucose (IFG) for a fasting plasma glucose level of 5.6–6.9 mmol/L
(100–125 mg/dL)
 Impaired glucose tolerance (IGT) for plasma glucose levels of 7.8–11.1 mmol/L (140–
199 mg/dL) 2 h after a 75-g oral glucose load
Individuals with IFG or IGT are at risk for developing type 2 DM and cardiovascular disease.
Screening with a fasting plasma glucose level is recommended every 3 years for those over
45 years old, overweight (BMI ≥25 kg/m2) and have additional risk factors [first-degree relative
with diabetes; physical inactivity; race (African American, Latino, Native American, Asian
American, Pacific Islander); previously identified IFG, IGT, or hemoglobin A1C 5.7–6.4%;
history of vascular disease, GDM or delivery of baby >4 kg (99 lb); hypertension; HDL
cholesterol level ≤0.90 mmol/L (35 mg/dL); triglyceride level ≥2.82 mmol/L (250 mg/dL); and
polycystic ovary syndrome or acanthosis nigricans].
Metabolic syndrome (insulin resistance syndrome or syndrome X) describe metabolic
derangements that includes insulin resistance (with or without diabetes), hypertension,
dyslipidemia, central or visceral obesity, and endothelial dysfunction and is associated with
accelerated cardiovascular disease.

Clinical Features
Common presenting symptoms include polyuria, polydipsia, weight loss, fatigue,
weakness, blurred vision, frequent superficial infections, and poor wound healing. In early type 2
DM, symptoms consist of fatigue, poor wound healing, and paresthesias. Lack of symptoms is
the main reason for the delayed diagnosis of type 2 DM. Complete medical history should be
obtained with special emphasis on weight, exercise, smoking, ethanol use, family history of DM,
and risk factors for cardiovascular disease. In patient with established DM, assessment of prior
diabetes care, HbA1c levels, self-monitoring blood glucose results, frequency of hypoglycemia,
and knowledge about DM should be obtained. Special attention should be given on physical
examination to retinal examination, BP, foot examination (vibratory sensation and monofilament
testing), peripheral pulses, and insulin injection sites.

Complications
Acute
o Diabetic ketoacidosis (type 1 DM)
DKA results from insulin deficiency with a relative or absolute increase in glucagon and
caused by inadequate insulin administration, infection (pneumonia, UTI, gastroenteritis, sepsis),
infarction (cerebral, coronary, mesenteric, peripheral), surgery, trauma, drugs (cocaine), or
pregnancy. Precipitating scenario: type 1 DM patient who erroneously stops administering
insulin because of anorexia/lack of food intake caused by minor illness, followed by lipolysis and
progressive ketosis leading to DKA.

Initial symptoms include anorexia, nausea, vomiting, polyuria, and thirst. Abdominal pain,
altered mental function, or frank coma may ensue. Classic signs of DKA include Kussmaul
respirations and acetone odor of breath. Volume depletion can lead to dry mucous membranes,
tachycardia, and hypotension. Fever and abdominal tenderness may also be present.
Laboratory evaluation: hyperglycemia, ketosis (β-hydroxybutyrate>acetoacetate), and metabolic
acidosis (arterial pH 6.8–7.3) with an increased anion gap. Fluid deficit is often 3–5 L and or
greater. Despite a total-body potassium deficit, serum potassium may be normal or mildly high
as a result of acidosis. Phosphate may be normal despite total-body phosphate depletion.
Leukocytosis, hypertriglyceridemia, and hyperlipoproteinemia are common. Hyperamylasemia is
of salivary origin but may suggest a diagnosis of pancreatitis. Serum sodium is reduced as a
consequence of osmotic fluid shifts due to hyperglycemia (1.6-meq reduction for each 5.6-
mmol/L [100-mg/dL] rise in the serum glucose).

1) Confirm diagnosis (plasma glucose, positive serum ketones, metabolic acidosis).

2) Admit to hospital; intensive-care setting may be necessary for frequent monitoring or if
pH <7.00 or unconscious.
3) Assess: Serum electrolytes (K+, Na+, Mg2+, Cl–, bicarbonate, phosphate) Acid-base
status—pH, HCO3–, PCO2, β-hydroxybutyrate renal function (creatinine, urine output)
4) Replace fluids: 2–3 L of 0.9% saline over first 1–3 h (10–15 mL/kg per hour);
subsequently, 0.45% saline at 150–300 mL/h; change to 5% glucose and 0.45% saline
at 100–200 mL/h when plasma glucose reaches 14 mmol/L (250 mg/dL).
5) Administer short-acting insulin: IV (0.1 units/kg) or IM (0.3 units/kg), then 0.1 units/kg per
hour by continuous IV infusion; increase two- to threefold if no response by 2–4 h. If
initial serum potassium is <3.3 meq/L, do not administer insulin until the potassium is
corrected to >3.3 meq/L. If the initial serum potassium is >5.2 meq/L, do not supplement
K+ until the potassium is corrected.
6) Assess: What precipitated the episode (noncompliance, infection, trauma, infarction,
cocaine)? Initiate appropriate workup for precipitating event (cultures, chest x-ray, ECG).
7) Measure capillary glucose every 1–2 h; measure electrolytes (especially K+,
bicarbonate, phosphate) and anion gap every 4 h for first 24 h.
8) Monitor blood pressure, pulse, respirations, mental status, fluid intake and output every
1–4 h.
9) Replace K+: 10 meq/h when plasma K+ <5.0–5.2 meq/L, ECG normal, urine flow and
normal creatinine documented; administer 40–80 meq/h when plasma K+ <3.5 meq/L or
 if bicarbonate is given. If initial serum potassium is >5.2 mmol/L (5.2 meq/L), do not
supplement K+ until the potassium is corrected.
10) Continue above until patient is stable, glucose goal is 150–250 mg/dL, and acidosis is
resolved. Insulin infusion may be decreased to 0.05–0.1 units/kg per hour.
11) Administer intermediate or long-acting insulin as soon as patient is eating. Allow for
overlap in insulin infusion and SC insulin injection.

o Hyperglycemic hyperosmolar state (type 2 DM)

Relative insulin deficiency and inadequate fluid intake are the underlying causes of HHS.
Hyperglycemia induces osmotic diuresis that leads to profound intravascular volume depletion.
HHS is often precipitated by concurrent illness such as myocardial infarction or sepsis and
compounded by conditions that impede access to water.

Presenting symptoms include polyuria, thirst, and altered mental state, ranging from lethargy
to coma. The prototypical patient is an elderly individual with several weeks history of polyuria,
weight loss, and diminished oral intake. In contrast to DKA, acidosis and ketonemia are usually
not found; however, a small anion gap may be due to lactic acidosis, and moderate ketonuria
may occur from starvation. Prerenal azotemia is typically present. Serum sodium may be normal
or slightly low, the corrected serum sodium is usually increased (add 1.6 meq to measured
sodium for each 5.6-mmol/L [100-mg/dL] rise in the serum glucose). HHS has significant
mortality rate (up to 15%), which is in part explained by comorbidities and patient age.

The precipitating problem should be sought and treated. Sufficient IV fluids (1–3 L of 0.9%
normal saline over the first 2–3 h) should be given to stabilize the hemodynamic status. The
calculated free water deficit (9–10 L) should be reversed over the next 1–2 days, using 0.45%
saline initially then 5% dextrose in water. Overly rapid fluid replacement should be avoided to
prevent worsening of neurologic status. Potassium repletion is usually necessary. Plasma
glucose may drop precipitously with hydration alone, though insulin therapy with an IV bolus of
0.1 units/kg followed by a constant infusion rate (0.1 units/kg per hour) is usually required. If the
serum glucose does not fall, insulin infusion rate should be doubled. Glucose should be added
to IV fluid, and the insulin infusion rate decreased when the plasma glucose falls to 13.9 mmol/L
(250 mg/dL). The insulin infusion should be continued until the patient has resumed eating and
can be transitioned to subcutaneous insulin regimen.
Complications
Chronic
o Ophthalmologic: nonproliferative or proliferative diabetic retinopathy, macular edema,
rubeosis of iris, glaucoma, cataracts
o Renal: proteinuria, end-stage renal disease, type IV RTA
o Neurologic: distal symmetric polyneuropathy, polyradiculopathy, mononeuropathy,
autonomic neuropathy
o Gastrointestinal: gastroparesis, diarrhea, constipation
o Genitourinary: cystopathy, erectile dysfunction, female sexual dysfunction, vaginal
candidiasis
o Cardiovascular: coronary artery disease, congestive heart failure, peripheral vascular
disease, stroke
o Lower extremity: foot deformity (hammer toe, claw toe, Charcot foot), ulceration,
amputation
o Dermatologic: Infections (folliculitis, furunculosis, cellulitis), necrobiosis, poor healing,
ulcers, gangrene
o Dental: Periodontal disease

Treatment
Optimal treatment requires more than plasma glucose management. Comprehensive
diabetes care should detect and manage DM-specific complications and modify risk factors for
DM-associated diseases. Those with type 1 or 2 DM should receive education about nutrition,
exercise, care of diabetes during illness, and medications to lower the plasma glucose. Target
HbA1c level should be <7.0%. Individual considerations (age, ability to implement complex
treatment regimen, and presence of other medical conditions) should be taken into account.
Intensive therapy is associated with more frequent and more severe hypoglycemic episodes.
Goal pre-prandial capillary plasma glucose levels should be 3.9–7.2 mmol/L (70–130 mg/dL)
and postprandial levels should be <10.0 mmol/L (<180 mg/dL) 1–2 h after a meal.
Those with type 1 DM require 0.5–1.0 U/kg/day of insulin divided into multiple doses.
Combinations of insulin preparations with different times of onset and duration of action should
be used. Preferred regimens: injection of glargine at bedtime with pre-prandial lispro, glulisine,
or insulin aspart or continuous SC insulin using infusion device. Pramlintide, an injectable
amylin analogue, as adjunct therapy to control postprandial glucose excursions.
Those with type 2 DM may be managed with diet and exercise alone or in conjunction
with oral glucose-lowering agents, insulin, or combination of oral agents and insulin. Exenatide
and liraglutide are injectable glucagon-like peptide 1 (an incretin) analogues that may be used in
combination with metformin or sulfonylureas. A reasonable treatment algorithm for initial therapy
proposes metformin as initial therapy because of its efficacy (1–2% decrease in HbA1c), known
side-effect profile, and relatively low cost. Metformin has the advantage that it promotes mild
weight loss, lowers insulin levels, improves the lipid profile slightly, lowers cancer risk, and does
not cause hypoglycemia when used as monotherapy. Metformin is contraindicated in renal
insufficiency, congestive heart failure, acidosis, liver disease, or severe hypoxia, and should be
temporarily discontinued in seriously ill patient or those receiving radiographic contrast material.
Metformin can be followed by addition of second oral agent (insulin secretagogue, DPP-IV
inhibitor, thiazolidinedione, α-glucosidase inhibitor, or SLGT2 inhibitor). Combinations of two
oral agents may be used with additive effects, with stepwise addition of bedtime insulin or a third
oral agent if adequate control is not achieved. As endogenous insulin production falls, multiple
injections of long-acting and short-acting insulin may be required, as in type 1 DM. Those who
require >1 U/kg per day of long-acting insulin should be considered for combination therapy with
insulin-sensitizing agent such as metformin or thiazolidinedione. Insulin-requiring type 2 DM
patients may also benefit from addition of pramlintide. Bariatric surgery in selected patients.
Optimal and individualized glycemic control:
o Self-monitoring of blood glucose (individualized frequency)
o HbA1c testing (2–4 times/year)
o Patient education (annual); diabetes self-management education and support
o Medical nutrition therapy and education (annual)
o Eye examination (annual or biannual)
o Foot examination (1–2 times/year by physician; daily by patient)
o Screening for diabetic nephropathy (annual)
o Blood pressure measurement (quarterly)
o Lipid profile and serum creatinine (estimate GFR) (annual)
o Influenza/pneumococcal/hepatitis B immunizations
o Antiplatelet therapy

Routine urinalysis as an initial screen for diabetic nephropathy. If it is (+) for protein,
quantification of protein on a 24-h urine collection should be performed. If the urinalysis is (-) for
protein, spot collection for microalbuminuria should be performed (present if 30–300 μg/mg
creatinine on two of three tests within 3- to 6-month period). Resting ECG should be performed
in adults, with more extensive cardiac testing for high-risk pts. Therapeutic goals to prevent
complications of DM include management of proteinuria with ACE inhibitor or angiotensin
receptor blocker therapy, BP control (<130/80 mmHg if no proteinuria, <125/75 if proteinuria),
and dyslipidemia management (LDL <2.6 mmol/L [<100 mg/dL], HDL >1.1 mmol/L [>40 mg/dL]
in men and >1.38 mmol/L [50 mg/dL] in women, triglycerides <1.7 mmol/L [<150 mg/dL]).
Diabetic patient >40 years should take statin, regardless of LDL cholesterol, and those with
existing cardiovascular disease, LDL target should be <1.8 mmol/L (70 mg/dL).

Management of the Hospitalized Patient

The goals of diabetes management during hospitalization are near-normal glycemic
control, avoidance of hypoglycemia, and transition back to the out-patient diabetes treatment
regimen. Patients with type 1 DM undergoing general anesthesia and surgery, or with serious
illness, should receive continuous insulin, either through an IV insulin infusion or by SC
administration of a reduced dose of long-acting insulin. Short-acting insulin alone is insufficient
to prevent the onset of DKA. Oral hypoglycemic agents should be discontinued in pts with type
2 DM at the time of hospitalization. Either regular insulin infusion (0.05–0.15 U/kg per hour) or a
reduced dose (by 30–50%) of long-acting insulin and short-acting insulin (held, or reduced by
30–50%), with infusion of a solution of 5% dextrose, should be administered when patients are
NPO for a procedure. Long- and short-acting SC insulin should be used in type 2 patients who
are eating. Glycemic goal for hospitalized pts with DM should be pre-prandial glucose of <7.8
mmol/L (<140 mg/dL) and <10 mmol/L (<180 mg/dL) at post-meal times. For critically ill, glucose
levels of 7.8–10.0 mmol/L (140–180 mg/dL) are recommended. Those with DM undergoing
radiographic procedures with contrast dye should be well hydrated before and after dye
exposure, and the serum creatinine should be monitored after the procedure.