Name: Emanuel Charles Coates

Registration #: 2018010033

Topic: Diabetes Mellitus – Diabetic Ketoacidosis

CASE: DIABETES MELLITUS – DIABETIC KETOACIDOSIS

A 16-year-old female patient presents to the emergency room complaining of vomiting

and abdominal pain. She has a 2-week history of frequent urination and refers being
thirsty all the time.

On examination, the patient is pyrexial (temperature 38.3°C), tachycardic (120

beats/min), and hypotensive (98/54 mmHg) with an oxygen saturation (SpO2) of 97%
on air. She appears dehydrated with a dry tongue, and her breath has a ‘fruity’ odour.
Heart auscultation and abdominal palpation are unremarkable. Her breathing is noted to
be rapid (respiratory rate 30 breaths/ min) and deep.

In the Emergency Department, a capillary blood sample registers high on the glucose
meter, and venous blood samples are sent for urgent laboratory estimations. Urinalysis
is also performed.

Learning Objectives (Anatomy, Physiology, Pharmacology and Biochemistry)

1. Identify the different endocrine and exocrine composition of the pancreas.

2. Understand the organization of B-cells membrane, receptors and its functions.
3. Compare the microscopic features of normal and pancreas affected with Type-
I and Type-II Diabetes.
4. Discuss the mechanism of secretion of Insulin and glucagon hormone
5. Briefly discuss the concept of insulin receptor.
6. Describe the factors affecting insulin, glucagon secretion and concept of
glycemic index.
7. What is the biochemical basis for all the presenting symptoms?
8. Classify Diabetes Mellitus
9. Discuss the clinical manifestations of new onset DM vs Diabetic Ketoacidosis
10. Understand how to make a diagnosis of Diabetes Mellitus and Diabetic
Ketoacidosis
11. Describe the types of Insulin preparations and their dose and duration of
action.
12. Explain the treatment of Diabetes Ketoacidosis.
 1. Identify the different endocrine and exocrine composition of the
pancreas.
The pancreas is a soft, lobulated organ that stretches obliquely across the posterior
abdominal wall in the epigastric region. It has a dual function, that’s exocrine and
endocrine functioning units.

The endocrine function of the pancreas is performed by the islets of Langerhans

collectively, the islets comprise only 1–2% of the pancreatic mass. The human pancreas
contains about 1 to 2 million islets. Histologically Islets of Langerhans consist of four
types of cells:
1. A cells or α-cells, which secrete glucagon comprise perhaps as much as 20% of
islet tissue which increase blood glucose through gluconeogenesis and
glycogenolysis.

2. B cells or β-cells, which secrete insulin make up about 60–75% of a typical islet
which decreases blood glucose through glycogenesis.

3. D cells or δ-cells, which secrete somatostatin which makes up 5-10% inhibits the
Islets hormone functions.

4. F cells or PP cells, which secrete pancreatic polypeptide rarer cell type which
inhibits pancreatic exocrine cell functions.

The structure of the exocrine pancreas resembles a cluster of grapes and its functional
units (acinar cells and ductule cells) are similar to the salivons of the salivary glands.
Pancreatic exocrine secretion consists of an enzymatic component and an aqueous or
bicarbonate component.
Histologically the secretory acini each have a single layer of acinar cells with a lumen in
the centre that’s surrounded by a basal lamina that is supported only by a delicate
sheath of reticular fibers with a rich capillary network. A small duct arises from lumen
of each alveolus extend into the lumen of the acinus as small pale-staining centroacinar
cells that are unique to the pancreas. These ducts from neighbouring alveoli unite to
form intralobular duct which unites to form the main duct of the pancreas called
Wirsung duct. Wirsung duct joins the common bile duct to form the ampulla of Vater.

1. The acinar cells comprise approximately 80% of the pancreas by volume and
secrete a small volume of juice containing the pancreatic enzymes (their site of
production) mediated by CCK.

2. Ductule cells, which comprise about 4% of the gland, together with the
centroacinar cells, secrete the aqueous component, a large volume secretion of
water and NaHCO3 mediated by Secretin.
 2. Understand the organization of B-cells membrane, receptors and its
functions.
Beta cells increase their rates of insulin secretion within 30 sec of exposure to increased
concentrations of glucose and can shut down secretion rapidly. B- cells are polygonal
cells containing secreting vesicles, they are widely distributed throughout the pancreas
and located centrally within the islet of Langerhans have high GLUT -2 channels on their
cell membrane which allows facilitated diffusion of glucose into the cell to be
phosphorylated. Some receptors located on B- cells of the pancreas:
1. The beta-cell has specific receptors for glucagon, acetylcholine, GLP-1, and other
compounds that increase insulin secretion by promoting the formation of cyclic
AMP or IP3 and DAG. Through the use of GPCR (G-Protein Coupled Receptor)
which is seven-transmembrane alpha- helix protein.
2. The ubiquitous vitamin D receptors are located in the β-cells of Islet of
Langerhans of the pancreas. It has been proposed that vitamin D probably
stimulates not only the release of insulin but also the expression of insulin
receptors. Studies have shown that low vitamin D levels may be a particular
problem for children and teenagers with Type-1 diabetes.

3. Compare the microscopic features of normal and pancreas affected with

Type-I and Type-II Diabetes.

A normal pancreas consists of numerous pale staining clusters of cells termed islets of
Langerhans scattered throughout the pancreas. There are four types of endocrine cells
in the islets of Langerhans which is difficult to distinguish among them in H&E stain
with the B-cells located centrally and secretes insulin within the fed state and
peripheral A-cells which secretes glucagon during the fasting state.

In type I diabetes mellitus due to autoimmune destruction of beta cells by T

lymphocytes
1. Characterized by early insulitis with marked islet atrophy and fibrosis and severe
beta-cell depletion
2. Associated with HLA-DR3 and HLA-DR4
3. Autoantibodies against insulin are often present

In type II diabetes mellitus is characterized by an early increase in insulin levels in the

disease, but later, insulin deficiency develops due to beta-cell exhaustion; histology
reveals amyloid deposition in the islets.
 4. Discuss the mechanism of secretion of Insulin and glucagon hormone

Mechanism of Insulin Secretion

The primary stimulant to insulin is the high levels of glucose in the blood. The B-cells of
the pancreas has high levels of GLUT 2 Channels and Glucokinase thus inulin secretion
is mediated by:
1. Increase levels of blood glucose.
2. Which diffuse into the pancreas through the GLUT 2 channel.
3. Glucose in the pancreatic B cells is phosphorylated by Glucokinase into glucose-
6-phosphate.
4. Thus glucose-6-phosphate oxidize to form ATP which inhibits the ATP-sensitive
potassium channel closing it.
5. Closure of potassium channel results in depolarization which causes the voltage-
gated calcium channels to open.
6. The influx of calcium results into the docked insulin-containing vesicle to fuse
with the cell membrane releasing insulin in the extracellular fluid. (exocytosis)

Mechanism of Glucagon Secretion

The mature glucagon molecule is the major secretory product of the α cell. As with
insulin, the fully processed glucagon molecule is stored in secretory vesicles within the
cell’s cytosol. Glucagon secretion is mediated by low levels of Blood glucose and high
levels of amino acids. Glucagon is packaged, stored in membrane-bound granules, and
secreted by exocytosis like other peptide hormones. Glucagon circulates without
binding to carrier proteins and has a half-life in blood of about 5 min.

5. Briefly discuss the concept of insulin receptor.

On the target cells, insulin binds with the receptor protein and forms the insulin-
receptor complex. This complex executes the action by activating the intracellular
enzyme system.
The insulin receptor is a tetramer, formed by four glycoprotein subunits (two α-
subunits and two β-subunits). With the α-subunits extended to the outside while the β-
subunits is extended to the inside linked together by disulphide bonds. The Intracellular
surfaces of α-subunits have the enzyme activity, tyrosine kinase activity.
When insulin binds with α-subunits of the receptor protein, the tyrosine kinase at the β-
subunit is activated by means of autophosphorylation. Thus, insulin action is exerted on
the target cells by the activation of some intracellular enzymes and by the inactivation
of other enzymes. GLUT 4 transporter is expressed through the insulin-receptor
complex on skeleton and adipose tissue cell membrane results in glucose uptake for
storage.
 6. Describe the factors affecting insulin, glucagon secretion and concept of
glycemic index.
The factors that stimulate insulin secretion are:
1. High levels of blood glucose, increase in fatty acid and after a meal (fed state)
2. Increase levels amino acid (The most potent of these amino acids are arginine
and lysine)
3. Incretins that are released after a meal such as GLP-1, GIP (gastrointestinal
hormone)
4. Insulin is secreted in response to hormonal levels such as glucagon, growth
hormone and cortisol.
5. Insulin secretion can be mediated by parasympathetic fibers in the vagus nerve
stimulate beta cells by releasing acetylcholine or the neuropeptide VIP.
6. The body resistance to insulin; obesity can result in the body producing more
insulin
7. Drugs such as Sulfonylurea drugs (glyburide, tolbutamide) results in increase
insulin levels
The factors that decrease insulin secretion are:
1. Decreased blood glucose (fasting state)
2. The release of somatostatin from D-cells
3. Neural through the release of norepinephrine and epinephrine
4. Hormonal through leptin, somatostatin
The factors that stimulate the release of glucagon:
1. Increased blood amino acids stimulate secretion of glucagon especially the
amino acids alanine and arginine. The importance of amino acid stimulation of
glucagon secretion is that the glucagon then promotes the rapid conversion of
the amino acids to glucose through gluconeogenesis.
2. Exercise stimulates the secretion of glucagon. during exhaustive exercise, blood
glucagon concentration often increases fivefold.
The factors that decrease glucagon release are:
1. Blood glucose concentration is by far the most potent factor that controls
glucagon secretion. Thus, increased blood glucose inhibits glucagon secretion.
2. The release of somatostatin from D-cells inhibits the release of glucagon.

Glycemic index
The glycemic index of a food is an indication of how rapidly blood glucose levels rise
after consumption. It is assessed by the glucose tolerance test (the glycemic response)
after the particular diet and comparing it with a reference meal. The reference meal is
always taken as 50 g of glucose.
Glucose and maltose have the highest glycemic indices, but the same quantity of
complex carbohydrates (such as starch) will not increase the blood glucose to the same
extent, because digestion and absorption are slow. Highly glycemic carbohydrates can
be consumed before and after exercise because their metabolism results in a rapid entry
of glucose into the blood, where it is then immediately available for use by muscle cells.
Low-glycemic carbohydrates enter the circulation slowly and can be used to best
advantage if consumed before exercise, such that as exercise progresses, glucose is
slowly being absorbed from the intestine into the circulation, where it can be used to
maintain blood glucose levels during the exercise period.
 7. What is the biochemical basis for all the presenting symptoms?

• Frequent urination also known as (polyuria). Large amounts of glucose may be

excreted in urine (maybe 90 to 100 G/day in some cases known as glucosuria).
As glucose reabsorption threshold is breached. Loss of solute produces osmotic
diuresis thus large volume of urine results in polyuria.

• Thirsty all the time is due to ketosis, develops anorexia, nausea, and vomiting.
Continued loss of water and electrolytes increases (dehydration). There the
patient develops polydipsia, due to the excess loss of fluid. Therefore, the patient
appears dehydrated with a dry tongue.

• Patient is pyrexial, diabetes can slow down the body ability to fight against
infection and higher levels of sugar in the blood results in the fast increase in
bacterial growth leading increase in body temperature.

• Hyperglycemia due to insulin deficiency causes an osmotic diuresis that leads

to marked urinary losses of water and electrolytes. Urinary excretion of
ketones obligates additional losses of sodium and potassium. This accounts for
the loss of blood volume through the means of severe dehydration resulting
into hypotension to compensate for the decreased blood pressure there is a
marked increase in heart rate(tachycardia) to increase the cardiac output and
bring the blood pressure to normal.

• The hyperglycaemia activates different signalling mechanisms such as an

increased polyol pathway (sorbitol pathway):- in chronic diabetes, there is an
increase in glucose that make use of this alternative pathway to decrease glucose
by forming fructose, however, there are some tissues (Schwann cells, Retina,
Nephrons) that lack the sorbitol dehydrogenase enzyme required to convert the
sorbitol to fructose thus result in diabetic complications in these tissues
(Neuropathy, Retinopathy, Nephropathy) as sorbitol(osmotically active) levels
increase. Other mechanisms:- advanced-glycation end products (AGEs)
formation, activation of Protein Kinase C (PKC) and hexosamine pathway leading
to overexpression of reactive oxygen species and subsequent development of a
diabetic complication.

• The liver converts free fatty acid to ketone bodies. If ketosis is severe, acetone
will be breathed out, giving characteristic “fruity” smell in-breath (due to
acetone) thus resulting in the appearance of the ‘fruity’ odour.

• Once Diabetic Ketoacidosis develops in the absence of insulin to reverse this

trend, using respiratory alkalosis to compensatory for the acidosis. This
mechanism results in the stimulation of the respiratory centre in the
hypothalamus, which leads to deeper and more frequent respiration (Kussmaul
breathing). CO2 is expired more rapidly than normal, and the blood pH rises
toward normal. Thus, accounting for her breathing to be rapid (respiratory rate
of 30 breaths/ min) and deep.
 8. Classify Diabetes Mellitus
Diabetes mellitus can be broken into groups Primary Diabetes mellitus, Secondary
Diabetes mellitus, Gestational Diabetes, and Special diabetes.
A. Primary Diabetes Mellitus (Idiopathic):
➢ Insulin-Dependent Type 1 Diabetes Mellitus (IDDM): - Due to
autoimmune disease that leads to absolute insulin deficiency or reduce
plasma insulin levels.
➢ Non- Insulin-Dependent Type 2 Diabetes Mellitus (NIDDM): - Associated
with progressive loss of beta-cell insulin secretion capacity and or
peripheral insulin resistance
Other forms of Type 2 diabetes
• Pre-diabetes can lead to the development of (NIDDM)
B. Secondary Diabetes Mellitus (cause by other diseases):
➢ Pancreatic diabetes
• Pancreatitis
• Haemochromatosis
• Malignancy of Pancreas.
➢ Abnormal concentrations of antagonistic hormones:
• Hyperthyroidism
• Hypercorticism: like Cushing’s disease and syndrome
• Acromegaly
C. Gestational Diabetes: - Gestational diabetes mellitus (GDM) may be associated
with hormonal imbalance; it is normally diagnosed in the second or third
trimester in pregnant women with no clear overt DM prior to gestation.
D. Special Type according to (WHO classification)
➢ Maturity onset diabetes: -Maturity-onset type diabetes of the young
(MODY) was previously considered to be a third form of type 2 diabetes.
However, with the discovery of specific mutations leading to MODY, it is
now classified under secondary or other specific types of diabetes. MODY
is characterized by onset prior to age 25. All cases to date have shown
impaired β-cell function. Patients may also exhibit insulin resistance and
late β-cell failure. Evidence indicates that mutations in at least 14
different genes have been correlated with the development of various
forms of MODY.
➢ Latent autoimmune diabetes in adults (LADA): - is a slow-progressing
form of autoimmune diabetes. Like the autoimmune disease type
1 diabetes, LADA occurs because your pancreas stops producing adequate
insulin, most likely from some "insult" that slowly damages the insulin-
producing cells in the pancreas. But unlike type 1 diabetes, with LADA,
you often won't need insulin for several months up to years after you've
been diagnosed.
 9. Discuss the clinical manifestations of new-onset DM vs Diabetic
Ketoacidosis?
New-Onset Diabetes
Patients often present with
abdominal pain and weight loss,
sometimes accompanied by jaundice and
deep vein thrombosis. The above signs
may be the first indication of an occult
pancreatic cancer in older patients;
abnormal glucose tolerance
There is a bidirectional relationship
between Covid-19 and diabetes which.
Thus, it is plausible that SARS-CoV-2 may
cause pleiotropic alterations of glucose
metabolism that could complicate the
pathophysiology of pre-existing diabetes
or lead to new mechanisms of disease.
Viral infection can also account can
induce autoimmunity thus associating in
the new onset diabetes. Example
cytomegalovirus
New-onset diabetes mellitus after
transplantation (NODAT) is the
occurrence of diabetes mellitus
in a previously nondiabetic person after
solid organ transplantation
some of the clinical features remain the
include elevated blood glucose and body
resistance to insulin.
Diabetic Ketoacidosis
Risk for diabetic ketoacidosis
Characterized by excessive serum ketone
Often arises with stress (e.g., infection);
epinephrine stimulates glucagon
secretion increasing lipolysis (along with
gluconeogenesis and glycogenolysis).
Increased lipolysis leads to increased free
fatty acids (FFAs). Liver converts FFAs to
ketone bodies (~-hydroxybutyric acid
and acetoacetic acid).
Clinical Manifestation of diabetic
ketoacidosis include: -
• Fruity- smelly breath
• Vomiting
• Abdominal pain
• Deep slow (Kussmaul) breathing,
• Change in mental status (including
coma),
• Elevated blood glucose
• Elevated urinary ketones
• an arterial blood pH lower than
7.3, and low bicarbonate (15
mmol/L).
 10. Understand how to make a diagnosis of Diabetes Mellitus and
Diabetic Ketoacidosis
A diagnosis of Diabetes Mellitus should not be made based on one abnormal glucose
concentration. According to the (WHO) standard, four diagnostic tests for diabetes are
currently recommended:
1. Fasting blood glucose
2. Postprandial blood glucose
3. 2-hour (2-h) post-load plasma glucose after a 75 g oral glucose tolerance test
(OGTT)
4. Glycosylated (glycated) haemoglobin (HbA1c) most effective measurement for
blood glucose.
Individual with fasting plasma glucose values of ≥ 7.0 mmol/L (126 mg/dl) and a 2-h
post-load plasma glucose ≥ 11.1 mmol/L (200 mg/dl) With HbA1c ≥ 6.5% (48
mmol/mol); or a random blood glucose ≥ 11.1 mmol/L (200 mg/ dl) in the presence of
signs and symptoms are considered to have diabetes.

In the differential diagnosis of ketoacidosis, the urine of the patient will have a
positive Benedict test as well as positive Rothera’s test. However, in starvation, the
Benedict test is Negative while the Rothera’s test remains Positive.
In the diagnosis of ketoacidosis their parameters that need to be check are:
1. Arterial pH
2. Serum ketones
3. Calculation of Anion gap.
The patient is diagnosed with Diabetic Ketoacidosis when there is an arterial pH < 7.30
with an anion gap > 12 and serum ketones in the presence of hyperglycemia.
 11. Describe the types of Insulin preparations and their dose and
duration of action.
Insulin preparations are classified as rapid, short, intermediate, long-acting and
premixed.
Insulin preparation Onset(hr) Peak(hr) Duration(hr) Management Concentration

Rapid-acting
Insulin lispro 0.2-0.3 1-1.5 3-5 Covers insulin U100, U200
Insulin aspart 0.2-0.3 1-1.5 3-5 needs for meals U100
Insulin glulisine 0.2-0.4 1- 2 3-5 eaten at the U100
same time as
the injection
Short-acting
Regular (soluble) insulin 0.5-1 2-3 6-8 Covers insulin U100, U500
Novolin needs for meals
Velosulin 0.5-1 1-2 2-3 eaten within
30-60 minutes.
Intermediate-acting
Insulin zinc suspension or 1- 2 8- 10 12-20 Covers insulin
Lente needs for about
Neutral protamine 1-2 8- 10 12- 20 half the day or U100
hagedorn overnight.
(NPH) or isophane insulin
Long-acting
Insulin glargine 2-4 ----- 24 Covers insulin U100, U300
Insulin detemir 1-4 ----- 20-24 needs for about U100
Insulin degludec (Tresiba) 0.5-1 ----- 42 one full day. U100, U200
Pre-mixed
Humulin 70/30 0.5 2-4 14-24 These products U100
Novolin 70/30 0.5 2-12 Up to 24 are generally U100
Novolog 70/30 10-20 mins 1-4 Up to 24 taken two or U100
Humulin 50/50 0.5 2-5 18-24 three times a U100
Humalog mix 75/25 0.2 0.5 -2 1/2 16-20 day before U100
mealtime.

Premixed insulins combine specific amounts of intermediate-acting and short-acting insulin

in one bottle or insulin pen.
Good timing will help you avoid low blood sugar levels.

• Rapid-acting insulins: About 15 minutes before mealtime

• Short-acting insulins: 30 to 60 minutes before a meal
• Intermediate-acting insulins: Up to 1 hour prior to a meal
• Pre-mixed insulins: Depending on the product, between 10 minutes or 30 to 45
minutes before mealtime
 12. Explain the treatment of Diabetes Ketoacidosis.
Diabetic ketoacidosis (DKA) is a life-threatening medical emergency caused by inadequate
or absent insulin replacement, which occurs in people with type 1 diabetes and
infrequently in those with type 2 diabetes.

The fundamental treatment for DKA includes aggressive intravenous hydration and
insulin therapy and maintenance of potassium and other electrolyte levels. Fluid and
insulin therapy are based on the patient’s individual needs and requires frequent re-
evaluation and modification. Close attention must be given to hydration and renal status,
sodium and potassium levels, and the rate of correction of plasma glucose and plasma
osmolality. Fluid therapy generally begins with normal saline. Regular human insulin
should be used for intravenous therapy with a usual starting dosage of about 0.1 U/kg/h.

Insulin therapy: - Regular insulin is used to rapidly correct metabolic abnormalities. A

bolus dose of 0.1-0.2 U/kg intravenous is followed by 0. 1 U/kg/hr infusion; the rate is
doubled if no significant fall in blood glucose occurs in 2 hr.

Fluid replacement: - Correction of dehydration is vital. normal saline is infused

Intravenously, initially at the rate of I L/hr, reducing progressively to 0.5 L/4 hours
depending on the volume status. saline is the most appropriate fluid because blood glucose
falls before ketones are fully cleared from the circulation. Also, glucose is needed to restore
the depleted hepatic glycogen.

Electrolyte replacement:- Electrolyte replacement through an IV to replace

key minerals like sodium, potassium, and chloride to keep your heart, muscles, and nerves
working properly. When insulin therapy is instituted ketosis subsides and K+ is driven back
intracellularly- dangerous hypokalemia can occur. After 2- 3 hours, it is appropriate to add
10- 20 mEq/hr KCI to the (I.V) fluid.
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https://www.msdmanuals.com/professional/endocrine-and-metabolic-
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