1. Diabetes Mellitus Dr: Wael H.Mansy, MD Assistant Professor
College of Pharmacy
King Saud University

2. Diabetes Mellitus Study Objectives
• List the effects of insulin and glucagon in the body.
• List the factors that put an individual at risk for developing diabetes.
• Discuss the possible etiology of type I and type II diabetes.
• Define the three “ploys.” Why do they occur?
• What are the manifestations of diabetic ketoacidosis? Why does it occur?
• What is hyperosmolar -hyperglycemic syndrome? Why does it occur?
• Discuss pharmacologic and nonpharmacologic treatment for diabetes .
• Discuss possible mechanisms of tissue injury in diabetes mellitus.
• List the major effects of chronic diabetes mellitus. Why does each occur?
• Define gestational diabetes

3. Diabetes Mellitus
Group of metabolic disorders characterized by hyperglycemia resulting from either or both:
insufficient insulin secretion
resistance to the action of insulin
Abnormalities in carbohydrate, fat, protein metabolism

4. Effects of Insulin on Various Tissues
Adipose Tissue
Increased glucose entry
Increased fatty acid synthesis
Increased glycerol phosphate synthesis
Activation of lipoprotein lipase
Inhibition of hormone-sensitive lipase
Increased K+ uptake
Muscle
Increased glycogen synthesis
Increased amino acid uptake
Increased protein synthesis in ribosomes
Decreased release of gluconeogenic amino acids
Increased ketone uptake
Liver
Decreased ketogenesis
Increased protein synthesis
Increased lipid synthesis
Decreased glucose output due to decreased gluconeogenesis, increased glycogen synthesis, and increased glycolysis
General
Increased cell growth

5. Insulin stimulates hepatic glucose storage as glycogen; in adipose tissue as triglycerides; and amino acid storage in muscle as protein; it also promotes utilization of glucose in muscle for energy. These pathways, which also are enhanced by feeding, are indicated by the solid blue arrows. Insulin inhibits the breakdown of triglycerides, glycogen, & protein and conversion of amino acids to glucose (gluconeogenesis), as indicated by the white arrows. These pathways are increased during fasting and in diabetic states. Conversion of amino acids to glucose & glucose to fatty acids occurs primarily in the liver.

7. Diabetes Classification
Majority of diabetics classified in 2 categories:
type 1: absolute deficiency of insulin
type 2: presence of insulin resistance with reduced insulin secretion
Gestational diabetes
triggered by stress of pregnancy
Other specific types:
infections, drugs, endocrinopathies, pancreatic destruction, genetic defects 7

9. Type 1 DM Autoimmune destruction of pancreatic β-cells
~90% of patients have markers of immune β-cell destruction at diagnosis
children & adolescents often have rapid β-cell destruction & present with ketoacidosis
may occur at any age
Known as latent autoimmune diabetes in adults (LADA)
slowly progressive
sufficient insulin secretion to prevent ketoacidosis for many years 9

10. LADA
Latent Autoimmune Diabetes in Adults (LADA) is a form of autoimmune (type 1 diabetes) which is diagnosed in individuals who are older than the usual age of onset of type 1 diabetes.
Alternate terms that have been used for "LADA" include Late-onset Autoimmune Diabetes of Adulthood, "Slow Onset Type 1" diabetes, and sometimes also "Type 1.5
Often, patients with LADA are mistakenly thought to have type 2 diabetes, based on their age at the time of diagnosis.
Autoimmune (type 1 diabetes)
type 2 diabetes

11. LADA (cont.) (Islet Cell Antibodies)
(Glutamic Acid Decarboxylase Autoantibodies)

12. Type 1 DM Pathogenesis Preclinical period Hyperglycemia
immune markers present
β-cell destruction
Hyperglycemia
80 to 90% of β-cells destroyed
Transient remission
honeymoon phase
Established disease 12

13. Type 2 DM Insulin resistance, relative lack of insulin secretion
Usually presents with cluster of abnormalities known as metabolic syndrome:
abdominal obesity
hypertension
dyslipidemia
elevated PAI-1 (plasminogen activator inhibitor-1) levels
Increased macrovascular complication risk 13

14. NCEP ATP III: Components of the Metabolic Syndrome (> 3 for diagnosis)
Risk Factor
Defining Level
Abdominal obesitya
Men (waist circumference)b
> 102 cm (> 40 in.)
Women
> 88 cm (> 35 in.)
Triglycerides
> 1.7 mmol/L (> 150 mg/dL)
HDL cholesterol
Men
< 1.0 mmol/L (< 40 mg/dL)
< 1.3 mmol/L (< 50 mg/dL)
Blood Pressure
≥ 130/≥ 85 mmHg
Fasting glucose
> 6.1 mmol/L ( > 110 mg/dL)
NCEP-ATP: National Cholesterol Education Program Adult Treatment Panel

15. Screening Type 1 Type 2 not recommended low prevalence, acute symptoms
fasting plasma glucose (FPG) recommended
alternative: oral glucose tolerance test (OGTT)
more costly, less convenient, less reproducible
HbA1c (HbA1c reflects glucose levels for the previous 2 to 3 months)
no gold standard assay
useful in monitoring glycemic control after diagnosis 15

16. Glucose Tolerance Test
Blood glucose curves of a normal and a diabetic person after oral administration of 1 g of glucose/kg body weight.
Note the initial raised concentration in the fasting diabetic.
A criterion of normality is the return of the curve to the initial value within 2 hours.

17. ADA Type 2 Diabetes Screening Recommendations
Type 2 DM Screening
ADA Type 2 Diabetes Screening Recommendations
Children & Adolescents
Every 3 years at age 10 or onset of puberty if overweighta with two additional risk factorsb
Adults
Every 3 years in adults ≥ 45 years of age or earlier if overweightc & additional risk factors present
aBMI > 85th percentile for age & sex, > 85th percentile weight for height, or > 120% of ideal weight for height bFamily history of DM2 in 1st or 2nd degree relative; high risk ethnic group; signs of insulin resistance; maternal history of gestational diabetes during child’s gestation c BMI ≥ 25kg/m2
American Diabetes Association. Standards of medical care in diabetes Diabetes Care 2009;32:S13-S61.

18. Type 2 DM Risk Factors BMI ≥ 25 Physical inactivity
1st degree relative with DM
High risk ethnic group (Latino, African American, Native American, Asian American, Pacific Islander)
IFG, IGT
HTN: ≥ 140/90 mmHg or on therapy for HTN
CV disease
HDL < 35 mg/dL
Triglycerides > 250 mg/dL
Delivery of > 9 lb baby
History of GDM
Insulin resistance
Polycystic ovary syndrome
American Diabetes Association. Standards of medical care in diabetes Diabetes Care 2009;32:S13-S61.

19. Screening for Gestational DM
Risk assessment at 1st prenatal visit
Screen high risk women as soon as possible
family history of DM
history of GDM
marked obesity
presence of glycosuria
diagnosis of PCOS
If initial screening negative, retest high risk women at 24 to 28 weeks gestation 19
American Diabetes Association. Standards of medical care in diabetes Diabetes Care 2009;32:S13-S61.

20. Gestational diabetes mellitus
Any degree of glucose intolerance with onset or first recognition during pregnancy, most commonly seen during the third trimester of pregnancy (in about 1 to 6% of pregnancies).
More common among obese women and women with a family history of diabetes.
Resolves itself in most patients after birth but in certain percentage (50 to 60%) type 2 diabetes will develop within 10 yrs of initial diagnosis.
May be associated with an increased risk of fetal abnormalities.
Currently recommended that all pregnant women be screened for the presence of gestational diabetes.

21. Diagnosis Normal Impaired fasting glucose (IFG)
FPG < 100 mg/dL
2 hr postload plasma glucose < 140 mg/dL
Impaired fasting glucose (IFG)
FBG = 100 to 125 mg/dL
Impaired glucose tolerance (IGT)
2 hr postload plasma glucose = 140 to 199 mg/dL
Diabetes mellitus
FPG ≥ 126 mg/dL
2 hr postload plasma glucose ≥ 200 mg/dL

22. ADA Criteria for DM Diagnosis1
Fastinga plasma glucose (FBG) ≥ 126 mg/dL 2
Symptoms of diabetesb & casualc plasma glucose ≥ 200 mg/dL 3
2-hour plasma glucose ≥ 200 mg/dL during OGTTd
In absence of unequivocal hyperglycemia: confirm on different day
a Fasting: no caloric intake for at least 8 hours
b Classic symptoms: polyuria, polydipsia, unexplained weight loss
c Causal: any time of day without regard to last meal
d Oral glucose tolerance test: equivalent to 75-g anhydrous glucose in H2O; not recommended for routine clinical use
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:

24. Clinical Presentation of Diabetesa
Characteristic 
Type 1 DM 
Type 2 DM 
Age
< 30 yearsb
> 30 yearsb
Onset
Abrupt
Gradual
Body habitus
Lean
Obese or history of obesity
Insulin resistance
Absent
Present
Autoantibodies
Often present
Rarely present
Symptoms
Symptomaticc
Often asymptomatic
Ketones at diagnosis
Absentd
Need for insulin therapy
Immediate
Years after diagnosis
Acute complications
Diabetic ketoacidosis
Hyperosmolar hyperglycemic state
Microvascular complications at diagnosis No
Common
Macrovascular complications at or before diagnosis
Rare
aClinical presentation can vary widely. bAge of onset for type 1 DM is generally < 20 years of age but can present at any age. The prevalence of type 2 DM in children, adolescents, and young adults is increasing. This is especially true in ethnic and minority children. cType 1 can present acutely with symptoms of polyuria, nocturia, polydipisia, polyphagia, weight loss. dType 2 children and adolescents are more likely to present with ketones but after the acute phase can treated with oral agents. Prolonged fasting can also produce ketones in individuals.

25. Diabetes Mellitus Manifestations:
Symptoms of diabetes appear when the levels of glucose are either very high or very low.
Many persons with diabetes and all those with pre-diabetes do not have symptoms.
Children may also feel very tired all the time.

26. Diabetes Mellitus Manifestations: Weight loss.
The three “ploys” : Polydepsia (increased thirst),
Polyphagia (increased appetite),
Polyuria (increased urine output).
Weakness and fatigue due to poor energy utilization and skeletal muscle catabolism .

27. Diabetes Mellitus Why do the three “polys” occur?
Polyuria :Excess blood glucose filtered by the kidneys cannot be reabsorbed and is eliminated at the expense of water.
Polydepsia : Excessive thirst caused by the osmotic diuresis of glucose and subsequent tissue dehydration. The thirst response is mediated by the hypothalamus.
Polyphagia: Poor utilization of carbohydrates (due to the lack of insulin) results in depletion of stored fats, proteins and carbohydrates.

28. - INSULIN Fatty Acids INSULIN+
Diabetes Mellitus
Manifestations:
Diabetic ketoacidosis
Accumulation of acidic ketone bodies in the blood due to a lack of insulin stimulated fatty acid utilization. Much more common in type I than type 2
Ketone Bodies
(β-hydroxybutyrate)
(acetoacetate)
(acetone)
- INSULIN Fatty Acids INSULIN+
Energy

29. Diabetes Mellitus Manifestations:
Manifestations of Diabetic Ketoacidosis
Decreased blood pH levels.
Ketonuria — Appearance of excess ketones in the urine.
Lethargy.
Nausea and vomiting
Severe dehydration.
Markedly increased respiratory rate as an attempt to correct decreased blood pH.
Acetone breath — Acetone is a volatile ketone body that is eliminated via the lungs; may be noticeable in the exhaled air during diabetic ketoacidosis.
Coma and possible death.

30. Diabetes Mellitus Manifestations: Hyperglycemic Hyperosmolar Syndrome
A syndrome of type I diabetes mellitus that can result from acute insulin deficiency.
It may often accompany diabetic ketoacidosis.
The manifestations include:
Severe dehydration
Extreme thirst
Serum osmolarity over 300 mOsm due to excessive glucose in the blood
Osmotic diuresis of glucose
Depressed neurologic function
Possible shock, coma and death

31. Diabetes: Complications
Macrovascular
Microvascular
Stroke
Diabetic eye disease
(retinopathy and cataracts)
Heart disease and hypertension
2-4 X increased risk
Renal disease
Peripheral
vascular disease
Erectile Dysfunction
The risk of CAD and stroke is increased two to four times in patients with diabetes. Cardiovascular disease is a major cause of morbidity and mortality in diabetes. Morbidity and mortality rates are two to four times higher than in age- and sex-matched groups in the population without diabetes.
The eye and the kidney are common sites for microvascular complications of diabetes. Diabetic retinopathy is the leading cause of adult blindness in North America. Cataracts and glaucoma are also significantly more frequent in patients with diabetes, especially those over age 65. Diabetes is the leading cause of end-stage renal failure.
Foot problems, a frequent consequence of neuropathy and peripheral vascular disease, constitute a major complication. Diabetes is the leading cause of non-traumatic lower-extremity amputations in North America.
Peripheral Neuropathy
Foot problems
Meltzer et al. CMAJ 1998;20(Suppl 8):S1-S29.

32. Diabetes Mellitus Complication: 1.Vascular Diseases
Chronic diabetes mellitus is associated with significant increases in the incidence of coronary artery disease, cerebrovascular disease and peripheral vascular disease.
May be due to a number of factors including elevated serum lipid levels, vascular injury, and enhanced atherogenesis (formation of atherosclerotic lesions).
Coronary artery disease and stroke are significant sources of mortality and morbidity in patients with diabetes. Peripheral vascular disease can lead to gangrene and amputations (particularly of the toes and feet) in people suffering from diabetes.

33. Diabetes Mellitus Complication: 2.Diabetic neuropathy
Abnormality of nerve conduction and function.
Often affects peripheral nerves.
Can involve sensory or motor neurons.
May manifest as numbness, pain or sensory/motor impairment.
Often progressive and irreversible.
Although the exact cause is unknown, the neuropathy may be related to ischemia or altered nerve cell metabolism.

34. Diabetes Mellitus Complication: 3.Diabetic Retinopathy
Pathogenesis of DR:
The most serious consequence of long-term diabetes in terms of the eye is retinal damage.
The retina is a highly metabolic tissue that is especially vulnerable to the effects of chronic hypoxia and diabetes.
Hemorrhage of eye capillaries and chronic inflammation is common and can lead to increases in intraocular pressure that scar the retina and impair vision. This phenomenon is usually progressive and can lead to blindness.
Diabetes is also associated with an increased incidence of glaucoma and cataract formation.

35. Diabetes Mellitus
Complication:
Diabetic Retinopathy

36. Diabetes Mellitus Complication: 4.Diabetic Nephropathy
It is a progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli.
The glomerular injury is characterized by thickening of the glomerular basement membrane and glomerulosclerosis.
Although the exact etiology is unclear, trapping of glycosylated proteins in the glomeruli appears to be a key contributing factor.
The appearance of protein (albumin) in the urine is an early indicator of altered glomerular permeability (Microalbuminuria).
Renal function may continue to deteriorate as glomerular filtration decreases.
Signs and symptoms of renal failure will appear as renal function continues to decline.

37. Diabetes Mellitus Complication: 5. Impaired healing and
increased infections
As a result of peripheral vascular disease, injuries in patients with diabetes do not heal properly. Poor blood flow limits the delivery of leukocytes and oxygen to the injured area while impairing removal of debris and infectious organisms.
The high glucose levels serve as a nutrient to support the growth of microorganisms.
Patients with diabetes might also be more susceptible to physical injuries as a result of impaired vision and sensory perception.

38. Erectile dysfunction
Erectile dysfunction (ED, "male impotence") is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance.
Since penile erection is neurovascular process, diabetic patients usually suffer from vascular complications that affect penile blood flow as well as neuropathies that disturb the nervous control of penile erection.

39. Diabetes Mellitus Complication: 6. Diabetic Foot Pathogenesis:
Loss of protective sensation.
Starts distally and migrates proximally in “stocking” distribution.
Mostly affects forefoot ulceration.
It results from repeated improper shoe ware, deformity or injury by glass or any other objects.

40. Possible Mechanisms of Tissue Injury in Chronic D M
Diabetes Mellitus
Complication:
Possible Mechanisms of Tissue Injury in Chronic D M
Glycosylation of proteins : Attachment of glucose to proteins in the eye, blood vessel walls, and kidney membranes will change their structure and may lead to altered function and eventual damage of these tissues. Circulating glycosylated proteins may also be trapped in the glomeruli of the kidney, leading to inflammation and injury.
Formation of alcohol sugars e.g. sorbitol : Unlike glucose, alcohol sugars do not easily diffuse out of tissues. Because these alcohol sugars are osmotically active, they can lead to swelling and damage of tissues. The accumulation of other sugars such as galactose might also contribute to this phenomenon
Poor blood flow and oxygen delivery to tissues :Glycosylation of hemoglobin alters its affinity for oxygen while progressive vascular disease can reduce overall blood flow to tissues, leading to ischemic injury

41. Fasting Blood Glucose Test (FBG)* Glucose Tolerance Test (GTT) **
Diabetes Mellitus
Diagnosis :
Diagnosis Criteria
Normal
Pre diabetes
Diabetes
Fasting Blood Glucose Test (FBG)*
Less than
100
Between
More than or equal
to 126
Glucose Tolerance Test (GTT) **
140
Equal to or more than 140 but
less than 200
More than or equal to 200
* FBG blood test is done after fasting 8 hours.
** GTT results are repeated after 2 hours. A person drinks a 75 mg glucose solution before test. 100 mg for Pregnant women.

42. To maintain target blood glucose
Diabetes Mellitus
Treatment
Optimal diabetes control is a careful balance of Diet, Exercise, and Insulin and/or oral medication
GOAL:
To maintain target blood glucose

43. Diabetes Self-management
what a person with diabetes should do by her/himself to maintain control
meal plan (always eating healthy)
exercise moderately (eg. walking 30 minutes a day), Exercise may enhance glucose utilization and improve glucose control in patients with type II diabetes, thus reducing the risk of diabetic complications.

44. Treatment of diabetes mellitus
The key to optimal diabetes control is a careful balance or juggling of food, exercise, and insulin and/or oral medication.
As a general rule, insulin/oral medication and exercise/activity makes blood glucose levels go down.
Maintaining good blood glucose control is a constant juggling act, 24 hours a day, 7 days a week.

45. 2 to 3 portions
2 to 4 portions
Less than one portion
2 to 3 portions
3 to 5 portions
6 to 11 portions

46. Type I of diabetes mellitus
Treatment:
Insulin replacement.
Insulin must be administered by injection because an oral form would be degraded in the gastrointestinal tract.
Insulin is generally available in three preparations:
Short-acting form : Peak action in 2–4 hours, duration 6–8 hours.
Intermediate-acting form :Peak action in 6–12 hours, duration 12–24 hours.
Long-acting form : Peak action 8–24 hours, duration 24–36 hours.

47. Type II of diabetes mellitus
Oral therapy: prescribed after dietary control has been proven insufficient or if the client is highly symptomatic
Classifications:
Sulfonylureas
Meglitnide analogs
Biguanides
Alpha-glucosidse inhibitors
Thiazolidinedione antidiabetic agents

48. Monitoring of DM Frequent measurement of blood glucose levels
Measurement of glycosylated hemoglobin (Hb A1c, hemoglobin that has glucose bound to it) that forms at a rate that increases with increasing blood glucose, which is a useful measure of blood glucose control in patients with diabetes.

49. Why should we educate diabetics about diabetes?
BECAUSE…
Controlling Glucose Levels through Self Management Every 1% drop of A1C significantly reduces the risk of eye, kidney, and nerve complications
Controlling Blood Pressure  Will reduce the risk of heart disease or stroke by 33% to 50%.
Controlling Lipids (fats)  Will reduce cardiovascular complications by 20% to 50%.
Careful foot care  Will reduce amputations rates by 45% to 85%.
Careful eye care  Will reduce the development of severe vision loss by 50% - 60%.
Careful kidney care  Will reduce the decline in kidney function by 30% - 70%.

50. THANK YOU