1. A 30-year-old male was brought to the emergency room unconscious. He was diagnosed with diabetic ketoacidosis and hyperglycemic hyperosmolar state due to insulin deficiency and resistance. 2. Insulin is synthesized and packaged in the pancreas and regulates glucose metabolism by inhibiting glycogenolysis and gluconeogenesis while stimulating glucose uptake in tissues. 3. Hypoglycemia can occur due to impaired counterregulatory hormone response and behavioral defenses in diabetics compared to non-diabetics.

1. Pratap sagar Tiwari, MD, Internal Medcine,
Lecturer, NMCTH
UNDERSTANDING DIABETES..PART 1

2. CASE SUMMARY
• A 30 yrs old M was brought in ERD in the state of unconsciousness.
(Note: Coma is a symptom, not a diagnosis.)
Pic taken from http://censorbugbear-reports.blogspot.com/2010/03/shocking-neglect-of-comatose-patient-at.html

3. CAUSES OF COMA
Metabolic Coma Structural Coma
Hypoglycemia Stroke
DKA/ HONK Head injury/trauma
Toxins/poison/drugs Subarachnoid hemorrhage
Uremic encephalopthy Subdural/epidural hematoma
Hepatic encephalopathy Tumours
Infectious/sepsis
Hypoxia (anoxic brain injury)/hypercapnic
Hypo/hyperthermia
Electrolyte disturbances
Seizures
Myxedema coma/ Addisonian crisis

4. DEFINITIONS
• The normal state of consciousness comprises either the state
of wakefulness, awareness, or alertness.
• Clouding of consciousness is a very mild form of altered
mental status in which the patient has inattention and reduced
wakefulness.
• Confusional state is a more profound deficit that includes
disorientation, bewilderment, and difficulty following commands.
• Lethargy consists of severe drowsiness in which the patient can
be aroused by moderate stimuli and then drift back to sleep.

5. DEFINITIONS
• Obtundation is a state similar to lethargy in which the patient
has a lessened interest in the environment, slowed responses to
stimulation, and tends to sleep more than normal with
drowsiness in between sleep states.
• Stupor means that only vigorous and repeated stimuli will
arouse the individual, and when left undisturbed, the patient will
immediately lapse back to the unresponsive state.
• Coma is a state of unarousable unresponsiveness.

6. OTHERS
• [Sudden] cardiac arrest is the sudden cessation of
cardiac activity so that the victim becomes
unresponsive, with no normal breathing and no signs of
circulation.
• Sudden cardiac death (SCD) is an unexpected death
due to cardiac causes that occurs in a short time period
(generally within 1 hour of symptom onset) in a person
with known or unknown cardiac disease.
References: American College of Cardiology/American Heart Association Task Force on Clinical Data Standards ,
Buxton AE, Calkins H, et al. Circulation 2006; 114:2534.

7. CASE SUMMARY
• A 30 yrs old M was brought in ERD in the state of unconsciousness.
Pic taken from http://censorbugbear-reports.blogspot.com/2010/03/shocking-neglect-of-comatose-patient-at.html
1. Hypoglycemia due to Insulin
therapy /OHA
2. Diabetic ketoacidosis and
hyperosmolar hyperglycemic
state in adults

8. INSULIN SYNTHESIS AND SECRETION
Taken from Harrison 18th edition

9. INSULIN
• Insulin is a peptide hormone composed of 51 amino acids that is
synthesized, packaged, and secreted by pancreatic beta cells.
• Insulin is synthesized as preproinsulin in the ribosomes of the
rough endoplasmic reticulum.
• Preproinsulin is then cleaved to proinsulin, which is transported
to the Golgi apparatus where it is packaged into secretory
granules located close to the cell membrane.
• Proinsulin is cleaved into equimolar amounts of insulin and C-
peptide in the secretory granules .

10. REGULATION OF GLUCOSE HEMOSTASIS
Insulin has a number of effects on glucose metabolism, including:
• Inhibition of glycogenolysis and gluconeogenesis
• Increased glucose transport into fat and muscle
• Increased glycolysis in fat and muscle
• Stimulation of glycogen synthesis
• Glucagon acts on the liver, increasing glucose production by
stimulating both glycogenolysis and gluconeogenesis from
alanine, among other amino acids, and glycerol.

11. RESPONSE TO HYPOGLYCEMIA IN NORMAL
SUBJECTS
• In the fasting state, when glucose cannot be obtained from the
intestinal absorption of food, glucose counterregulatory
mechanisms prevent or rapidly correct falling plasma glucose
concentrations .
1. Counterregulatory defence
2. Behavioral defence

12. COUNTERREGULATORY HORMONES
• The 1st defense is a decrease in insulin secretion as plasma
glucose concentrations decline within the physiological range
(starting at an venous PG threshold of 80-85 mg/dL )
• The 2nd defense is an increase in glucagon secretion. (The
glycemic threshold for glucagon is 65 to 70 mg/dL )
• The 3rd is an increase in epinephrine secretion. Acting via beta-
2-adrenergic receptors, epinephrine has similar hepatic effects
as glucagon. (The threshold for epinephrine secretion is 65 to
70 mg/dL )
• Cortisol and growth hormone contribute only if the hypoglycemia
persists for several hours. These hormones limit glucose
utilization and enhance hepatic glucose production.

13. BEHAVIORAL DEFENSES
• The initial symptoms of sweating, anxiety, palpitations, hunger, and
tremor occur as the plasma glucose concentration falls below 55-65 mg/dL.
• These symptoms trigger the important behavioral defense, ie, the ingestion
of food.
• They are signaled largely by increased sympathetic neural activity.
• Hypoglycemia can also cause cognitive dysfunction, which occurs in
normal subjects at PG below 50 mg/dL. Cognitive dysfunction can impair
behavioral defenses. More severe neurologic symptoms, including
obtundation, seizures, and coma, occur with progressive hypoglycemia.
Profound and prolonged hypoglycemia can cause brain death.

14. RESPONSE TO HYPOGLYCEMIA IN DIABETES
• Impairment of behavioral and counterregulatory
responses.
• The main defense against hypoglycemia is increased
release of counterregulatory hormones (glucagon
and epinephrine), which raise plasma glucose
concentrations by stimulating glucose production and
by antagonizing the insulin-induced increase in glucose
utilization.

15. HYPOGLYCEMIA
• In patients without diabetes, hypoglycemia is a clinical
syndrome with diverse causes in which low plasma glucose
concentrations lead to symptoms and signs, and there is
resolution of the symptoms/signs when the plasma glucose
concentration is raised [1].
• In patients with diabetes, hypoglycemia is defined as all
episodes of an abnormally low plasma glucose concentration
(with or without symptoms) that expose the individual to harm.
Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice
Guideline. J Clin Endocrinol Metab 2009; 94:709.

16. SIGN/SYMPTOMS OF HYPOGLYCEMIA
Autonomic response (tends to occur with blood glucose below 55-65
mg/dL)
- Sweating , Tachycardia, palpitation
- Weakness, Hunger, Paresthesias
- Tremor, Nervousness
• Neuroglycopenia below 50 mg/dL (2.8 mmol/L)
- Irritability, Confusion
- Seizure, Occasionally, transient focal neurologic deficits
- Visual disturbance, Loss-of-consciousness

17. DKA
• DKA is an acute, major, life-threatening complication of diabetes
that mainly occurs in patients with type 1 DM, but it is not
uncommon in some patients with type 2 DM.
• This condition is a complex disordered metabolic state
characterized by hyperglycemia, ketoacidosis, and
ketonuria.
Hyperglycemia Ketoacidosis

18. DKA
Insulin def/ resistance
Inhibition of “insulin inhibition
of Glucagon”
↑ Glucagon
↑ fat/muscle breakdown
↑ Hepatic gluconeogenesis
↑ delivery of gluconeogenetic
precursors to Liver
↑ Glycerol/ Alanine

19. Glycosuria
↓ Glucose excretion
↓ GFR
Osmotic Diuresis
Volume Depletion
↑ Blood GLucose

20. Action of Insulin:
↑ utilisation of peripheral
glucose in skeletal muscle ↑ Blood Sugar
X
Insulin↓/ Resistance
(Note: Insulin resistance is a condition in which cells fail to respond to the
normal actions of the hormone insulin. The body produces insulin, but the
cells in the body become resistant to insulin and are unable to use it as
effectively, leading to hyperglycemia.)

21. Insulin def/ resistance
Glucose utilization is impaired
Alternate source of Energy :
KETONES
↑ Lipolysis
TG
FFA
Normally
Plus increased
catecholamines

22. DEVELOPMENT OF KETOACIDOSIS
• The development of ketoacidosis requires a specific alteration in hepatic
metabolism so that free fatty acyl CoA can enter the mitochondria, where
conversion to ketones occurs.
• Mitochondrial entry is regulated by the cytosolic
enzyme carnitine palmitoyltransferase I (CPT I), the activity of which varies inversely
with malonyl CoA [1].
• Glucagon decreases the production of malonyl CoA, thereby increasing CPT I
activity and ketogenesis [2].
• Insulin does not appear to directly affect hepatic ketogenesis [3].
1. McGarry JD, Woeltje KF, Kuwajima M, Foster DW. Regulation of ketogenesis and the renaissance of carnitine palmitoyltransferase. Diabetes Metab Rev 1989;
5:271.
2. Cook GA, Nielsen RC, Hawkins RA, et al. Effect of glucagon on hepatic malonyl coenzyme A concentration and on lipid synthesis. J Biol Chem 1977; 252:4421.
3. Miles JM, Haymond MW.. Effects of free fatty acid availability, glucagon excess, and insulin deficiency on ketone body production in postabsorptive man. J Clin
Invest 1983; 71:1554.

23. NOTE
• Moderate insulin deficiency, as seen in HHS,
might be associated with sufficient insulin to
block lipolysis (and therefore ketoacid formation)
but not enough to promote glucose utilization
and prevent the development of hyperglycemia
[1].
1. Hillman K. Fluid resuscitation in diabetic emergencies--a reappraisal. Intensive
Care Med 1987; 13:4.

24. BREATHING PATTERNS: CHEYNE-STOKE
• characterized by periods of respirations during which the tidal
volume starts shallow and gets progressively deeper, and then
gets progressively shallower.
• This shallow-deep-shallow pattern is followed by periods of
significant apnea that can last up to 30 seconds or longer, then
the cycle starts over.

25. BIOT’S BREATHING (CLUSTER RESPIRATION)
• A respiratory pattern characterized by periods or
“clusters” of rapid respirations of near equal depth or
followed by regular periods of apnea.
• damage to the medulla oblongata by stroke (CVA) or
trauma.

26. ATAXIA RESPIRATIONS
• Completely irregular breathing pattern with irregular pauses and
increasing episodes of apnea.
• caused by damage to the medulla oblongata secondary to
trauma or stroke.

27. KUSSMAUL’S RESPIRATIONS
• A type of labored or hyperventilation characterized by a
consistently deep and rapid respiratory pattern.
• Most of the time a respiratory pattern secondary to a metabolic
acidosis is rapid and shallow and a true kussmaul breathing
pattern is rarely reached before the acidosis is corrected

28. APNEUSTIC RESPIRATIONS
• have a prolonged inspiratory phase followed by a prolonged
expiratory phase commonly believed to be apneic phases.
• damage to the upper part of the pons

29. FEATURES OF HYPEROSMOLARITY
• Excessive thirst despite frequently taking water / other liquids
• Continued high level of blood sugar
• Dry and/ or parched mouth
• Frequency of urination increases
• Pulse rate becomes rapid
• Shortness of breath with exertion
• Skin becomes dry and warm and there is no sweating
• Sleepiness and/ or a condition of confusion
http://www.mayoclinic.org/diseases-conditions/diabetic-hyperosmolar-syndrome/basics/definition/con-20026142

30. DIABETES MELLITUS
• Diabetes mellitus is a clinical syndrome characterised by
hyperglycaemia caused by absolute or relative deficiency of
insulin.

31. END OF SLIDES
References:
1. Harrison's Principles of Internal Medicine, 18th Edition
2. Davidson Practice of Medicine
3. Uptodate 20.3
4. Standards of Medical Care in Diabetesd 2014. American Diabetes Association. Diabetes
Care Volume 37, Supplement 1, January 2014
5. Medscape.com
6. Mercksmanual