C-Endocrine Disorders

Diabetes Mellitus
Diabetes mellitus (DM) is a group of metabolic diseases characterized by
hyperglycemia resulting from defects in insulin secretion, insulin action, or both (1).
Pathophysiology
There are two main types of diabetes: type 1 and type 2.
1-Type 1 diabetes (accounts for <10%), is caused by destruction of the insulin-
producing β-cells of the pancreas (2) (leading to absolute deficiency of insulin
secretion) (3).

2-Type 2 diabetes (accounts for about 90%), results from lack of sufficient insulin
production and/or lack of sensitivity to the effects of insulin (insulin resistance) (2).

Table 1: Differences between type 1 and type 2 diabetes (4, 5).

Type 1 Type 2
Endogenous Absent(Absolute insulin deficiency) Present(relative or partial
insulin insulin deficiency)
Age at onset Usually <30 yr Usually >40 yr
Body weight Patients usually not overweight Patients usually overweight
Acute Extreme hyperglycaemia causes Extreme hyperglycaemia
complication diabetic ketoacidosis (DKA) causes hyperosmolar
hyperglycaemic state

Clinical presentation
1. Symptom severity and onset help differentiate type 1 from type 2 DM.
a. Type 1 DM typically presents with an abrupt onset and an acute
presentation (3).
b. Symptoms in individuals with type 2 DM generally develop gradually,
with some patients being asymptomatic or having only mild symptoms upon
diagnosis (3).

2. Classic signs and symptoms of DM include polydipsia (excessive thirst) ,

polyuria (excessive urination) , polyphagia (excessive hunger ) (3) .

3. Individuals with type 1 DM may additionally present with unintentional weight

loss (3),(significant weight loss is less common in type 2 DM) (5).

Diagnosis (5, 6)
Criteria for the diagnosis of DM include any one of the following:
1. Hemoglobin A1C ≥6.5%.
2. Fasting (defined as no caloric intake for at least 8 hours) plasma glucose ≥126
mg/dL (7.0 mmol/L).
3. Two-hour plasma glucose ≥200 mg/ dL (111.1 mmol/L) during an oral glucose
tolerance test (OGTT) .

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4. A random plasma glucose concentration ≥200 mg/dL (111.1 mmol/L) in a
patient with classic symptoms of diabetes (Polyuria, polydipsla, unexplained
weight loss).
Note: The diagnosis must be confirmed by repeating the test, preferably the same
test (7).
Treatment
1- There are three major components to the treatment of diabetes: diet, drugs
(insulin and antidiabetic agents ), and exercise (7).

2-Appropriate treatment requires goal setting for glycemia, blood pressure, and
lipid levels (5). The American Diabetes Association (ADA) metabolic goals for
adults with diabetes mellitus are listed in Table 2 (8).

Note: Lower systolic targets, such as ,<130 mmHg, may be appropriate for certain individuals,
such as younger patients,if it can be achieved without undue treatment burden (8).

Pharmacotherapy of type 1 diabetes mellitus (9).

All patients with type I DM require insulin, Two regimens are commonly used:
basal-bolus and twice daily.
A-Basal-bolus regimens The dose of insulin is 0.5-1 unit/kg /day , 50% given
as basal insulin( long- or intermediate-acting insulins ) once or twice daily and
50% as fast-acting insulin (regular insulin, lispro, aspart, or glulisine )
divided into 3 equal doses and administered prior to meals. This provides a
pattern of insulin delivery similar to that in normal individuals.

B-Twice daily injections (before breakfast and before the evening meal) of pre-
mixed preparations of short- and intermediate-acting insulin provide a
convenience for many patients. Two-thirds of the daily dose given in the
morning (with about two thirds given as long-acting insulin and one-third as

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short-acting) and one-third in the evening (with approximately one-half given as
long-acting insulin and one-half as short-acting).

Table 3: Types of insulins (7).

Note : Supplemental doses of rapid-acting insulin are administered to acutely

lower glucose concentrations that exceed the target glucose concentration. These
doses must be individualized for each patient . (7) A general approach is to give an
additional 1 to 2 units of supplemental rapid-acting insulin for each to 50-mg/dL
elevation above the target level. or using the equation:
[body weight in kg] × [ (measured blood glucose level – desired glucose level in
mg/dL)/1500]. (9)

Hypoglycemia(7)
Definition
Blood glucose concentration <60 mg/dL: Patient may or may not be symptomatic
Blood glucose <40 mg/dL: Patient is generally symptomatic
Blood glucose <20 mg/dL: Can be associated with seizures and coma

urgent treatment of hypoglycemia(9)

If the patient is able to eat, oral treatment with or glucose-containing fluids, candy,
or food is appropriate. A reasonable initial dose is 15–20 g of glucose. If the
patient is unable to to take carbohydrates orally, parenteral therapy is used . IV
administration of glucose 25 g (mL of 50% dextrose for 1–3 minutes ) should be
followed by a glucose infusion with serial plasma glucose measurements. If IV
therapy is not practical, SC or IM glucagon (1 mg in adults) can be used,
particularly in patients with T1DM.
The somatostatin analogue octreotide can be used to suppress insulin secretion in
sulfonylurea-induced hypoglycemia. These treatments raise plasma glucose
concentrations only transiently, and patients should eat as soon as is possible to
replete glycogen stores.

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Diabetic Ketoacidosis(DKA) (9)
Definitions
Is a condition characterized by hyperglycemia (serum glucose > 250 mg/dL,
ketosis, and metabolic acidosis (serum bicarbonate <15 mmol/L with increased
anion gap).

Precipitating events(9)
Inadequate insulin administration, Infection ,Infarction and stressful conditions .

Management Of Diabetic Ketoacidosis (9)

TABLE 397-8 Management of Diabetic s
1-initially fluid replacement: 2–3 L of 0.9% saline over first 1–3 h (10–20 mL/kg
per hour); subsequently,0.9 %or 0.45% saline at 250–500 mL/h; change to5%
glucose and 0.45% saline at 150–250 mL/h when plasma glucose reaches 250
mg/dL

2-Administeration of short-acting regular insulin: IV (0.1 units/kg) bolus , then

0.1 units/kg per hour by continuous IV infusion .If the initial serum potassium is
<3.3 mmol/L, insulin should not be administered until the potassium is corrected.

3-Measurement of capillary glucose every 1–2 h; measure electrolytes (especially

K+, bicarbonate, phosphate) and anion gap every 4 h for first 24 h,Monitor blood
pressure, pulse, respirations, mental status, fluid intake and output every 1–4 h.

4-potassium Replacement : 20–40 meq/L of infusion fluid, with monitoring of

ECG and urine output.

5-if the patient is stable, glucose level is 150–200 mg/dL, and acidosis is
resolved. Insulin infusion may be decreased, long-acting insulin is given as soon
as patient is able to eat. Allow for a 2–4 hour overlap in insulin infusion and SC
long-acting insulin injection..

6-treatment of the underlying cause that precipitate DKA like infection ,

myocardial infraction or trauma.

Pharmacotherapy of type 2 diabetes mellitus

1-In patients with type 2 diabetes, first-line therapy involves advice about dietary
and lifestyle modification. Oral anti-diabetic drugs are usually added in those who
do not achieve glycaemic targets as a result, or who have severe symptomatic
hyperglycaemia at diagnosis and a high HbA1c (8).

2-However, the guidelines in some countries are to introduce medication

immediately upon diagnosis of diabetes (8).

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3-Table 4 lists classes of drugs for type 2 DM (6).

3-A reasonable treatment algorithm for initial therapy uses metformin as initial
therapy because of its efficacy, known side-effect profile, and relatively low cost
(Fig. 1). Metformin has the advantage that it promotes mild weight loss, and
improves the lipid profile slightly (9). However, type 2 DM is a progressive
disorder and ultimately requires multiple therapeutic agents and often insulin (9).

Table 4 :classes of drugs for type 2 DM

Drug Type Examples
Biguanides Metformin

Sulfonylureas Glipizide , Glimepiride, Glibenclamide

Dipeptidyl peptidase IV Sitagliptin , Saxagliptin, Linagliptin,

Alogliptin, vildagliptin
(DPP-IV) inhibitors
Thiazolidinediones Pioglitazone

Glinides Nateglinide, Repaglinide

α-Glucosidase Inhibitors Acarbose, Miglitol

Incretins Exenatide, Liraglutide,semaglutide

Amylin agonist Pramlintide

Bile Acid Sequestrant Colesevalem

Dopamine Agonist Bromocriptine

sodium-glucose cotransporter Canagliflozin, empagliflozin ,dapagliflozin

2 (SGLT-2) Inhibitor

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 Figure 1 : Glycemic management of type 2 diabetes. Agents that
can be combined with metformin include insulin secretagogues,
thiazolidinediones, α-glucosidase inhibitors, DPP-IV inhibitors, and GLP-1
receptor agonists.
Treatment of complications
1-Retinopathy
• Early retinopathy may reverse with improved glycemic control. More advanced
disease may requires laser therapy (4).

2-Neuropathy (4).
A- Peripheral neuropathy is the most common complication in type 2 DM
outpatients. Paresthesias, numbness, or pain may be predominant symptoms.
Pharmacologic therapy include duloxetine(the preferred one), low-dose
TCAs, anticonvulsants (e.g., gabapentin, pregabalin), , topical capsaicin, and
various analgesics, , including tramadol and NSAIDS.

B- Gastroparesis : use of metoclopramide may be helpful.

C- Patients with orthostatic hypotension may require mineralocorticoids
(fludrocortisone)
D- Diabetic diarrhea: is commonly nocturnal and frequently responds to a 10-
to 14-day course of an antibiotic such as doxycycline or metronidazole.
Octreotide may be useful in unresponsive cases.

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 E-Erectile dysfunction: is common, and initial treatment should include one of
the oral medications (e.g., sildenafil, vardenafil, tadalafil).

3-Nephropathy (4).
• Glucose and blood pressure control are most important for prevention of
nephropathy.
• ACE inhibitors and ARBs have shown efficacy in preventing the clinical
progression of renal disease in patients with type 2 DM.

4-Peripheral Vascular Disease and Foot Ulcers (4).

• Claudication and nonhealing foot ulcers are common in type 2 DM. Smoking
cessation, correction of dyslipidemia, and antiplatelet therapy are important
treatment strategies.
• Cilostazol may be useful in selected patients.

5-Coronary Heart Disease (4, 10).

• Multiple-risk-factor intervention [treatment of dyslipidemia (usually with a
statin) and hypertension (a goal BP of <140/80 mm Hg), smoking cessation,
antiplatelet therapy] reduces macrovascular events.

References
1- Cooper, Daniel H.; Krainik, Andrew J.; Lubner, Sam J.; Reno, Hilary E. L. Washington Manual of
Medical Therapeutics, The, 35th Edition 2016
2-Nadia Bukhari , David Kearney .Fasttrack therapeutics . First edition 2009 by pharmaceutical press.
3-Leon Shargel , Alan H. Mutnick . Comprehensive pharmacy review. Fifth edition 2007.
4- Roger Walker. Clinical Pharmacy and Therapeutics. Fifth edition 2012.
5- Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic Approach, 8th Edition. Copyright 2011.
6- Rick D .Kellerman,David P.Rakel. Conn’s Current Therapy. Copyright 2019
7-Caroline S. Zeind ,Michael G. Carvalho.Applied Therapeutic,The Clinical Use Of Drugs.11th Edition 2018
8- Stuart H Ralston, Ian D Penman, Mark WJ Strachan, Richard P Hobson. Davidson's Principles and Pracrtice of
Medicines . 23nd Edition 2018..
9- Dan L. Longo, et al, eds. Harrison's Principles of Internal Medicine, 20th Edition. 2018 .
10- American Diabetes Association. Standards of Medical Care in Diabetes 2014. Diabetes Care Volume 37,
Supplement 1, January 2014.

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