Exercise 8: Diabetes Mellitus 2

A.) Explanation of Clinical Database

- 40 year old = is the usual onset of DM Type 2

Although the prevalence of both type 1 and type 2 DM is increasing worldwide, the prevalence of type 2 DM is rising much
more rapidly, presumably because of increasing obesity, reduced activity levels as countries become more industrialized,
and the aging of the population… Worldwide, most individuals with diabetes are between the ages of 40 and 59 years.
Ch. 417: Diabetes Mellitus: Diagnosis, Classification, and Pathophysiology, Part 16: Endocrinology and Metabolism,
Harrison’s Principles of Internal Medicine 19th Ed.

- Obese/Obesity = is an established risk factor in the development of DM Type 2

- Fasting Blood Sugar (FBS) is 300mg/dL = is nearly double than the normally accepted level

- Both father and mother are diabetics = is an established risk factor in the development of DM Type 2
(refer to Table 417-3: Risk factors for Type 2 Diabetes Mellitus)

B.) Learning Objectives:

1. Discuss the role of insulin and glucagon on CHO metabolism

Normal glucose homeostasis is tightly regulated by three interrelated processes: glucose production in the liver; glucose
uptake and utilization by peripheral tissues, chiefly skeletal muscle; and actions of insulin and counter-regulatory
hormones, including glucagon, on glucose uptake and metabolism.
Insulin and glucagon have opposing regulatory effects on glucose homeostasis. During fasting states, low insulin and high
glucagon levels facilitate hepatic gluconeogenesis and glycogenolysis (glycogen breakdown) while decreasing glycogen
synthesis, thereby preventing hypoglycemia. Thus, fasting plasma glucose levels are determined primarily by hepatic
glucose output. Following a meal, insulin levels rise and glucagon levels fall in response to the large glucose load. Insulin
promotes glucose uptake and utilization in tissues (discussed later). The skeletal muscle is the major insulin-responsive
site for postprandial glucose utilization, and is critical for preventing hyperglycemia and maintaining glucose homeostasis.
Diabetes Mellitus from Kumar, Glucose Homeostasis, Robbins and Cotrans Pathologic Basis of Disease 8th Ed.

2. Describe the mechanism of glucose transport in the different cells of the body specifically in the
skeletal muscle, liver, and adipose tissues:

Glucose transport to the different cells of the body is regulated by glucose transporters (i.e. GLUTs). Take note also that
Liver cells are freely permeable to glucose (via the GLUT 2 transporter), whereas cells of extrahepatic tissues (apart from
pancreatic beta-islets) are relatively impermeable, and their glucose transporters are regulated by insulin

IMPT: Uptake from the bloodstream is the rate-limiting step in the utilization of glucose in extrahepatic tissues.
Ch. 20: Gluconeogenesis and the control of Blood Glucose, Metabolic and Hormonal Mechanisms Regulate the
Concentration of Blood Glucose, Harper’s Illustrated Biochemistry, 28 th Ed.

3. List the different metabolic pathways involved in maintaining a normal blood sugar level:
- Glycogenolysis
- Glycolysis
- Pyruvate oxidation
- Gluconeogenesis

4. Define Diabetes Mellitus Type 2

Insulin resistance and abnormal insulin secretion are central to the development of type 2 DM. Although the p rimary
defect is controversial, most studies support the view that insulin resistance precedes an insulin secretory defect but that
diabetes develops only when insulin secretion becomes inadequate. Type 2 DM likely encompasses a range of disorders
with common phenotype of hyperglycemia. C h. 417:Type 2 DM, Part 16: Endocrinology and Metabolism, Harrison’s
Principles of Internal Medicine 19th Ed.

5. State the signs and symptoms of Diabetes Mellitus Type 2:

- Polyuria - Seizures
- Polydipsia - Obtundation
- Obesity (Truncal or the “apple-shaped” morphology) - Severe volume depletion
- Lethargy - Orthostatic hypertension
- Coma (i.e. Hyperosmolar Nonketotic Coma)
6. Discuss the pathophysiology of Diabetes Mellitus Type 2:

Type 2 DM is characterized by impaired insulin secretion, insulin resistance, excessive hepatic glucose production, and
abnormal fat metabolism: Ch. 417: Type 2 DM Metabolic Abnormalities, Endocrinology and Metabolism, Harrison’s
Principles of Internal Medicine 19th Ed.

a.) Abnormal Muscle and fat Metabolism – Insulin resistance impairs glucose utilization by insulin-sensitive
tissues and increases hepatic glucose output; both effects contribute to the hyperglycemia. Increased hepatic glucose
output predominantly accounts for increased FPG levels, whereas decreased peripheral glucose usage results in
postprandial hyperglycemia. In skeletal muscle, there is a greater impairment in nonoxidative glucose usage (glycogen
formation) than in oxidative glucose metabolism through glycolysis. Glucose metabolism in insulin-independent tissues is
not altered in type 2 DM.

b.) Impaired Insulin Secretion – In type 2 DM, insulin secretion initially increases in response to insulin resistance
to maintain normal glucose tolerance. Initially, the insulin secretory defect is mild and selectively involves glucose-
stimulated insulin secretion, including a greatly reduced first secretory phase. The response to other nonglucose
secretagogues, such as arginine, is preserved, but overall beta function is reduced by as much as 50% at the onset of
type 2 DM. Abnormalities in proinsulin processing are reflected by increased secretion of proinsulin in type 2
DM. Eventually, the insulin secretory defect is progressive.

c.) Insulin resistance – The insulin resistance condition comprises a spectrum of disorders, with hyperglycemia
representing one of the most readily diagnosed features. Individuals with the type A insulin resistance syndrome have an
undefined defect in the insulin-signaling pathway; individuals with the type B insulin resistance syndrome have
autoantibodies directed at the insulin receptor. These receptor autoantibodies may block insulin binding or may stimulate
the insulin receptor, leading to intermittent hypoglycemia.

d.) Excessive Hepatic Glucose production – In type 2 DM, insulin resistance in the liver reflects the failure of
hyperinsulinemia to suppress gluconeogenesis, which results in fasting hyperglycemia and decreased glycogen storage
by the liver in the postprandial state. Increased hepatic glucose production occurs early in the course of diabetes,
although likely after the onset of insulin secretory abnormalities and insulin resistance in skeletal muscle.

7. Explain the biochemical basis of hyperglycemia among patients with impaired glucose tolerance:
- refer to 6.c. Insulin resistance for answer

8. State the different laboratory tests used in the diagnosis of DM Type 2:

- HbA1c
- Random Fasting Blood Sugar (RFBS)
- Oral Glucose Tolerance Test (OGTT)

9. Interpret the FBS result of the patient:

- Fasting Blood Sugar (FBS) is 300mg/dL = is nearly double than the normally accepted level (i.e. 126mg/dL).
refer to Clinical Database table 417-2: Criteria for the Diagnosis of Diabetes Mellitus

10. Define Oral Glucose Tolerance Test and its significance and describe how it is performed:
- OGTT is a test used to check how one’s body breaks down sugar

- Sample of blood will be taken Drink liquid containing 75g of Glucose

Another blood sample is taken procedure is repeated every 30 to 60min

- The OGTT procedure normally takes up to 3hrs

- OGTT Significance: The significance of the OGTT is that it allows the physician to test for the possibility of DM
(Diabetes Mellitus) in the patient, specifically the Type 2 (Insulin tolerant) kind of DM. The OGTT is also used to test for
Gestational DM for pregnant mothers between 24-28 weeks of pregnancy

11. Define Postprandial blood sugar; describe how it is performed and its clinical value:
 - The word postprandial means after a meal; therefore, PPG concentrations refer to plasma glucose
concentrations after eating. PPG levels are normally used to determine the individuals’ blood glucose level after a meal
and compare it with the normal values to check if he/she is nondiabetic or diabetic
- For a 2-hour postprandial test, a meal is eaten exactly 2 hours before the blood sample is taken. A home blood
sugar test is the most common way to check 2-hour postprandial blood sugar levels.

12. Define HbA1c and state its significance:

- Is also known as glycated or glycosylated Hb. In the blood there are 3 types of distinguishable types of Hb and
one of them is HbA, which is composed of 2α2β and is the dominant type in adults accounting for 96% of total Hb. HbA
has 4 subtypes, namely HbA1a1, HbA1a2, HbA1b, and of course, HbA1c. This specific subtype is monitored using the
A1c test and is seen in increased levels in DM (Diabetes Mellitus) patients as a result of increased blood glucose levels.
HbA1c is formed when blood glucose enters the erythrocyte where it glycates the ε-amino group of Lys residue
and the α-amino terminals of Hb in the erythrocyte. The fraction of Hb glycated, normally about 5% is proportionate to
blood glucose concentration. Since the half-life of an erythrocyte is typically 60days, the level of HbA1c reflects the mean
blood glucose concentration over the preceding 6-8weeks. Measurement of HbA1c, therefore provides valuable
information for management of DM.

13. State the complications of uncontrolled Diabetes Mellitus Type 2

Ch. 419: Diabetes Mellitus Complications, Endocrinology and Metabolism, Harrison’s Principles of Internal Medicine 19 th
Ed.

14. Discuss the biochemical mechanisms involved in the development of complication of Diabetes
Mellitus Type 2: (Four theories based on Harrison’s 19th)

1. Increased intracellular glucose leads to the formation of advanced glycosylation end products, which bind to a
cell surface receptor, via the nonenzymatic glycosylation of intra- and extracellular proteins, leading to cross-linking of
proteins, accelerated atherosclerosis, glomerular dysfunction, endothelial dysfunction, and altered extracellular matrix
composition.
2. Hyperglycemia increases glucose metabolism via the sorbitol pathway related to the enzyme aldose reductase.
However, testing of this theory in humans, using aldose reductase inhibitors, has not demonstrated beneficial effects.
3. Hyperglycemia increases the formation of diacylglycerol, leading to activation of protein kinase C, which alters
the transcription of genes for fibronectin, type IV collagen, contractile proteins, and extracellular matrix proteins in
endothelial cells and neurons.
4. Hyperglycemia increases the flux through the hexosamine pathway, which generates fructose-6-phosphate, a
substrate for O-linked glycosylation and proteoglycan production, leading to altered function by glycosylation of proteins
such as endothelial nitric oxide synthase or by changes in gene expression of transforming growth factor β (TGF-β) or
plasminogen activator inhibitor-1.

Ch. 419: Diabetes Mellitus Complications: Mechanisms of Complications, Endocrinology and Metabolism, Harrison’s
Principles of Internal Medicine 19th Ed.