1. Diabetus Mellitus & Hypoglycemia

2. Diabetes Mellitus
Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from:
an absolute deficiency of insulin secretion
or a reduction in the biologic effectiveness of insulin
or both
The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of different organs, especially the eyes, kidneys, nerves, heart, and blood vessels

3. Classification
In 1997, an international committee of diabetologists recommended a classification of diabetes that have been endorsed by the American Diabetes Association and the World Health Organization
Type 1 diabetes
B cell destruction, usually leading to absolute insulin deficiency
Immune-mediated
Idiopathic

4. Classification Type 2 diabetes Other specific types
may range from predominantly insulin resistance with relative insulin deficiency
to a predominantly secretory defect with insulin resistance
Other specific types
Genetic defects of B cell function
Genetic defects in insulin action
Diseases of the exocrine pancreas
Endocrinopathies
Drug- or chemical-induced
Infections
Uncommon forms of immune-mediated diabetes
Other genetic syndromes sometimes associated with diabetes
Gestational diabetes mellitus (GDM)

5. Type 1 Diabetes Mellitus
This form of diabetes is immune-mediated in more than 90% of cases and idiopathic in less than 10%
Diabetes mellitus type 1 occurs at any age but most commonly arises in children and young adults with a peak incidence before school age and again at around puberty
Most patients with type 1 diabetes at diagnosis have circulating antibodies:
islet cell antibody (ICA)
Insulin autoantibody (IAA)
antibody to glutamic acid decarboxylase (GAD) 65
localized within pancreatic beta cells
and antibody to tyrosine phosphatases IA2

6. Genetics & Environmental Factors of Type 1 Diabetes
Genetic influences are less marked in type 1 diabetes than in type 2 diabetes
Only 30–40% of identical twins of type 1 diabetic patients develop the disease
Type 1 diabetes is believed to result from an infectious or toxic environmental insult to genetically predisposed persons whose aggressive immune system destroys pancreatic β cells while overcoming the invasive agent
Environmental factors that have been associated with altered pancreatic islet cell function include
viruses (mumps, rubella)
Toxic chemical agents such as hydrogen cyanide

7. Type 1 Diabetes Mellitus
It is a catabolic disorder
Circulating insulin is virtually absent, plasma glucagon is elevated, and the pancreatic β cells fail to respond to all known insulinogenic stimuli
In the absence of insulin, the three main target tissues of insulin (liver, muscle, and fat)
fail to appropriately take up absorbed nutrients
and continue to deliver glucose, amino acids, and fatty acids into the blood from storage depots
alterations in fat metabolism lead to the production and accumulation of ketones

8. Type 2 Diabetes
Individuals with insulin resistance who generally have relative rather than absolute insulin deficiency
Accounts for 80–90% of cases of diabetes in the United States
Patients are usually adults over age 40 with some degree of obesity
They do not require insulin to survive, although over time their insulin secretory capacity tends to deteriorate, and many need insulin treatment to achieve optimal glucose control
Ketosis seldom occurs suddenly, and if present, it is a consequence of severe stress from trauma or infection

9. The Pathophysiology of Type 2 Diabetes
Islet
Insulin deficiency
Alpha cell
produces excess glucagon
Beta cell
produces less insulin
Pancreas
The pathophysiology of hyperglycemia in type 2 diabetes involves three main defects: (1) insulin deficiency due to insufficient pancreatic insulin release; (2) excess hepatic glucose output; and (3) insulin resistance (decreased glucose uptake) in peripheral tissues (including muscle and fat) and the liver.1-3
Two pancreatic islet cell defects contribute to this pathology:
Beta cells produce insulin, which facilitates glucose entry into tissues.4 In type 2 diabetes mellitus, a decline in functional beta-cell mass causes insulin deficiency, which in turn contributes to hyperglycemia.3-5
Alpha cells produce glucagon.6 Elevated glucagon levels promote increased hepatic glucose output.1
In type 2 diabetes mellitus, excess glucagon and diminished insulin secretion drive hepatic glucose output and contribute to hyperglycemia.1
Diminished insulin
Excess glucagon
Hyperglycemia
Muscle and fat
Excess glucose output
Insulin resistance (decreased glucose uptake)
Liver
Adapted from Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483; Buchanan TA Clin Ther 2003;25(suppl B):B32–B46; Powers AC. In: Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill, 2005:2152–2180; Rhodes CJ Science 2005;307:380–384.
References
Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR, Kronenberg HM, Melmed S et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders, 2003:1427–1483.
Buchanan TA. Pancreatic beta-cell loss and preservation in type 2 diabetes. Clin Ther 2003;25(suppl B):B32–B46. 
Powers AC. Diabetes mellitus. In: Kasper DL, Braunwald E, Fauci A et al, eds. Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill, 2005:2152–2180. 
Del Prato S, Marchetti P. Targeting insulin resistance and β-cell dysfunction: The role of thiazolidinediones. Diabetes Technol Ther 2004;6:719–731.
Rhodes CJ. Type 2 diabetes—a matter of β-cell life and death? Science 2005;307:380–384.
Williams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed. Malden, Massachusetts: Blackwell Publishing, 2004.

10. The Pathophysiology of Type 2 Diabetes
Tissue insensitivity to insulin has been noted in most patients with type 2 disease irrespective of weight and has been attributed to several interrelated factors
These include a genetic factor, which is aggravated in time by further enhancers of insulin resistance such as:
aging
a sedentary lifestyle,
and abdominal visceral obesity

11. The Pathophysiology of Type 2 Diabetes
In addition, there is an accompanying deficiency in the response of pancreatic β cells to glucose due to deposition of intraislet amyloid with aging
Type 2 diabetes frequently goes undiagnosed for many years, because the hyperglycemia develops quite gradually and is generally asymptomatic initially
These patients are at increased risk of developing macrovascular and microvascular complications

12. Insulin Resistance in Type 2 Diabetes
Insulin resistance can be broadly defined as a decrease in tissue responsiveness to insulin
Clinically it can be assessed directly by:
measuring the ability of a fixed dose of insulin to promote total body glucose disposal
It can be assessed indirectly by measuring fasting insulin levels
An increase in insulin levels with normal plasma glucose indicates insulin resistance

13. Insulin Resistance in Type 2 Diabetes
As adiposity increases, especially abdominal fat deposits, total body insulin sensitivity decreases
Adipose tissue only removes a small fraction of plasma glucose
Therefore, the increased adipose fat stores impact total body insulin sensitivity through effects on other tissues, especially muscle and liver, causing them to decrease insulin-stimulated glucose disposal
The exact means by which fat storage in adipocytes affects the insulin sensitivity of other cells remains uncertain

14. Possible Mechanisms of Insulin Resistance
Abnormalities of insulin receptors in concentration, affinity, or both affect insulin action
Target tissues regulate the number of insulin receptors on the cell by increased intracellular degradation
Conditions associated with high insulin levels and lowered insulin binding to the receptor include:
obesity, high intake of carbohydrates, and chronic exogenous over insulinization
Conditions associated with low insulin levels and increased insulin binding include exercise and fasting
The insulin receptor itself is probably not the major determinant of insulin sensitivity
Clinically relevant insulin resistance most commonly results from defects in postreceptor intracellular signaling pathways

15. Gestational diabetes mellitus
Glucose intolerance that is induced by pregnancy
Caused by metabolic and hormonal changes related to the pregnancy
Glucose tolerance usually returns to normal after delivery
An increased risk for development of diabetes in later years

16. Signs and symptoms of DM
Polydipsia (excessive thirst),
Polyphagia (increased food intake),
Polyuria (excessive urine production),
Rapid weight loss,
Hyperventilation,
Mental confusion,

17. Ketoacidosis
The individual with type 1 diabetes has a higher tendency to produce ketones (Beta-hydroxybutyrate, Acetoacetate, Acetone)
Absence of insulin and with increased glucagon leads to gluconeogenesis and lipolysis
The liver thus produces large amounts of ketone bodies, which are moderately strong acids
The result is severe acidosis
the decrease in pH impairs tissue function, most importantly in the central nervous system
In the absence of cellular glucose, fatty acids are oxidized for production of energy. Ketones are by-products of excessive beta-oxidation
of fatty acids

18. Hyperosmolar Nonketonic States
Type 2: have very little ketone production, but have a greater tendency to develop hyperosmolar nonketonic states
This disorder is caused by elevated blood sugar levels and is usually brought on by a coexisting condition, such as an illness or infection
The condition is characterized by hyperglycemia, hyperosmolarity, and dehydration without significant ketoacidosis
It can be a life-threatening emergency
hyperosmolar nonketonic states is one of two serious metabolic derangements that occurs in patients with diabetes mellitus and can be a life-threatening emergency.

19. Laboratory tests Glucose Glycosylated Hemoglobulin (HbA1c)
Ketone Bodies
Serum osmolality
Electrolytes
Microalbuminuria

20. Criteria For Diagnosis Of DM1.
Random plasma glucose ≥ 200 mg/dL (≥11.1 mmol/L), + symptoms of diabetes 2.
Fasting plasma glucose ≥ 126 mg/dL (≥7.0 mmol/L) 3.
Two-h plasma glucose ≥ 200 mg/dL (≥11.1 mmol/L) during an OGTT
Each of which must be confirmed on a subsequent day by any one of the three methods
N.B. To convert mmol/l of glucose to mg/dl, multiply by 18

21. Categories Of Fasting Plasma Glucose (FPG)
Normal fasting glucose
FPG <100 mg/dL (<5.6 mmol/L)
Impaired fasting glucose
FPG mg/dL ( mmol/L)
Provisional diabetes diagnosis
FPG ≥ 126 mg/dL (≤7.0 mmol/L)*
* Must be confirmed

22. Glycated Hemoglobin (HbA1c)
Correlations of HbA1c Levels with Average of Capillary Glucose Measurements (Preprandial, Postprandial, and Bedtime) in the Previous 3 Months
HbA1c Value (%)
Mean Capillary Blood Glucose Levels (mg/dL) 5 97 6
126 7
154 8
183 9
212 10
240 11
269 12
298

23. Differential Diagnosis
An attempt should be made to characterize the diabetes as type 1 or type 2 based on:
the clinical features present
and on whether ketonuria accompanies the glycosuria
For the occasional patient, measurement of ICAs, including ICA 512, and GAD and insulin antibodies can help in distinguishing between type 1 and type 2 diabetes

24. Treatment of Diabetes Mellitus
Plasma glucose
-Glucosidase Inhibitors
Glitazones
Carbohydrate
Absorption
Glucose
Uptake
(–)
(+)
Glucose
Production
GI tract
Muscle/Fat
(+)
Injected Insulin
Metformin
(–)
Liver
(–)
Slide 4-5
Antihyperglycemic Agents:
Major Sites of Action
The abnormalities in blood glucose regulation that characterize type 2 diabetes mellitus are complex and involve defects in insulin secretion as well as insulin resistance. The complexity of the metabolic defects in this condition has led to the development of therapeutic agents that affect different targets along the metabolic pathways involved. Plasma glucose may be lowered via the stimulation of insulin secretion by the sulfonylureas or the meglitinides, as well as by the stimulation of glucose uptake by muscle and fat, or by the decrease in hepatic production of glucose mediated by metformin or insulin. Acarbose and miglitol may decrease plasma glucose by slowing absorption of glucose from the gastrointestinal tract; the thiazolidinediones lower plasma glucose by enhancing tissue uptake of glucose. – +
Insulin
Secretion
Sulfonylureas
Meglitinides
Insulin
Secretion
(+)
Pancreas

25. Hypoglycemic Disorders

26. Hypoglycemia Hypoglycaemia, means “low blood glucose” (< 70 mg/dl)
It can arise from many causes, and can occur at any age
If too low can be life threatening (< 30 mg/dl)
Most effective on the CNS
there is shaking and tremors, heart rate increases- dizziness, cold sweat, if not corrected can result in unconsciousness-coma and death
Epinephrine act with glucagon to increase plasma glucose
The plasma glucose concentration at which glucagon and other glycemic factors are released is between 65 and 70 mg/dL
In addition cortisol and GH are also released

27. Hypoglycemia
The most common forms of moderate and severe hypoglycaemia occur as a complication of treatment of diabetes with insulin or blood glucose-lowering medicines
Risk increases with:
Consuming too little carbohydrate
Missing a meal or eating a meal later than the usual time
Prolonged or unplanned physical activity

28. Fasting hypoglycemia Hypoglycemia that occurs after fasting is rare
May occur as a response:
to insulin-producing tumors of the pancreas (insulinomas)
hepatic dysfunction,
glucocorticoid deficiency,
sepsis,
or low glycogen stores
Itypoglycaemia is sometimes seen in patients with
septicaemia. It is thought to be a result of the release of
cytokines, which may stimulate insulin secretion or
have a direct effect on hepatic glucose production.