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[answered] LAB 10: DIABETES CASE CONFERENCE Objectives: By the end of


Examine the laboratory data for Case I.? List all the abnormal values and arrive at a
??? ?biochemical explanation for why each of these values is abnormal.

2.? Why is glycosylated hemoglobin (HbA1c) level elevated in Case I? ?Why is this parameter useful
????? in monitoring diabetes and its treatment, i.e., what does it tell you??

Serum albumin is also easily glycosylated.? It has an average lifetime in the circulation of about 25 days.? In view of what you know about glycosylated hemoglobin and the life-span of erythrocytes that contain it, how would information you get from monitoring glycosylated albumin levels differ from that derived from glycosylated hemoglobin levels??

3.? Four major abnormalities are listed on page 6 as being characteristic of Type I diabetes.? For each
??? ?abnormality, explain why and how these abnormalities develop.? You may need to use your lecture
???? slides from carbohydrate metabolism, or consult a biochemistry textbook or online source.?

4.? Consider Donnatella in Case II.? Examine her lab data, the oral glucose tolerance test results, and her
??? ?insulin levels during this test. ?Is Donnatella diabetic? ?Does she have a problem with insulin
???? production and/or secretion?? Is she insulin-resistant??

5.? Examine Donnatella's diet.? What might you suggest to her to improve her diet and her overall
???? physical condition??

??? ?Two months after being seen at the clinic, Donnatella returned for additional tests.? She heeded
??? ?your advice, she lost 15 pounds, and she had been exercising regularly.? Results of her OGTT and
??? ?insulin levels are given below.?

6.? Is Donnatella diabetic? Does she still have any problems or abnormalities?? If so, what are they?
??? ?What might you expect her glycosylated hemoglobin levels to be on her return visit?? Why?


LAB 10: DIABETES CASE CONFERENCE

 

Objectives: By the end of this lab session, you should:

 

1. Understand insulin-dependent diabetes (IDDM)

 

2. Understand what is currently known about non-insulin dependent diabetes (NIDDM)

 

3. Understand the general mechanism by which insulin results in increased glucose uptake

 

3. Understand the role of insulin in controlling carbohydrate and lipid metabolism

 

4. Understand the basis for the metabolic acidosis and ketosis associated with IDDM

 

CASE 1: INSULIN-DEPENDENT DIABETES HISTORY:

 

Tyler F, a 17-year old high school student, was brought to the emergency room in a coma. His mother

 

said that her 6' 2", 175-pound son was physically active, and was a starting tight end on the high school

 

football team. However, during the past month, he had lost 12 pounds. She also had noticed that he

 

was excessively thirsty, drinking larger than normal quantities of Gatorade and fruit juices. Tyler also

 

urinated voluminously, voiding several times during the night. The admitting physician immediately

 

drew a blood sample and ordered blood gas and other analyses. A urine sample was also obtained and

 

analyzed with a Multistix dipstick. The results of the urinalysis showed a 5+ reaction for glucose

 

(=1000-2000 mg/dL), a 4+ reaction for ketone bodies (=80 mg/dL), and a specific gravity of 1.030

 

(normal range = 1.003 - 1.030). Results of a physical examination were basically negative, except for

 

moderate hyperventilation.

 

LABORATORY DATA

 

Patient

 

Arterial blood gases tests (upon admission)

 

pH

 

7.23

 

pCO2

 

30 mm Hg

 

?

 

HCO3

 

12 mEq/L

 

Serum glucose

 

1100 mg/dL

 

Serum Osmolality (~ specific gravity)

 

440 mOsm/kg

 

Serum lactate dehydrogenase (LD)

 

121 U/mL

 

Serum AST (liver marker)

 

24 U/mL

 

Serum ALT (liver marker)

 

35 U/mL

 

Serum bilirubin (Hb breakdown marker)

 

1.1 mg dL Normal Range

 

7.35 - 7.45

 

35-45 mm Hg

 

22-26 mEq/L

 

65-120 mg/dL

 

275-300 mOsm/kg

 

100-150 U/mL

 

8-30 U/mL

 

10-50 U/mL

 

0.2-1.2 mg/dL The symptoms and lab data were what would be expected for hyperglycemic ketoacidosis associated

 

with diabetes mellitus. The blood gas analyses on admission were consistent with metabolic acidosis

 

with partial respiratory compensation. Upon further discussion with the mother, it was learned that

 

two of her brothers and several uncles were diagnosed as having diabetes.

 

The patient was treated in the emergency room with intravenous insulin and intravenous fluids, and he

 

was admitted to the hospital. Later test results during hospitalization are shown below.

 

Patient Normal Range Serum glucose tests (post-admission)

 

Fasting

 

2-hour post-prandial 250 mg/dL

 

500 mg/dL 70-115 mg/dL

 

<140 mg/dL Oral glucose tolerance test

 

Fasting

 

30 minutes

 

1 hour

 

2 hours

 

3 hours

 

4 hours 150 mg/dL

 

300 mg/dL

 

325 mg/dL

 

390 mg/dL

 

300 mg/dL

 

260 mg/dL 70-115 mg/dL

 

<200 mg/dL

 

<200 mg/dL

 

<140 mg/dL

 

70-115 mg/dL

 

70-115 mg/dL 9% 2.2 - 4.8% Glycosylated hemoglobin During the first 72 hours of hospitalization, the patient was monitored by frequent serum glucose

 

determinations, and insulin was administered according to the results of these tests. The patient's

 

condition was eventually stabilized with 40 units of neutral protamine Hagedorn insulin/day. The

 

patient was given comprehensive instruction on self-blood glucose monitoring, insulin administration,

 

diet, exercise, and recognition of signs and symptoms of hypoglycemia and hyperglycemia, and he was

 

discharged one week after admission.

 

CASE 2: NON-INSULIN DEPENDENT DIABETES

 

HISTORY:

 

Donnatella C., a 28-year old mother of 2 children, applied for a new life insurance policy after her

 

husband died. She truthfully told the insurance company that she had an elevated serum glucose

 

concentration during her second pregnancy, and that her 58-year old mother had developed kidney

 

failure after a 20-year history of non-insulin-dependent diabetes mellitus (NIDDM). Donnatella was

 

told be the insurance company that she was not insurable because she had a "pre-existing condition",

 

namely, diabetes.

 

Donnatella visited her physician, who performed a physical examination. The results of the exam were

 

in the normal range, except for a calculated body-mass index (BMI) of 30. The BMI relates a person?s

 

weight to their height and compares the value with the value for the population at large. A BMI of 30

 

indicates that Donnatella is somewhat overweight for her height.

 

The following laboratory tests were also obtained:

 

Urine glucose

 

Urine protein

 

Fasting plasma glucose

 

2hr post-prandial glucose

 

glycosylated hemoglobin

 

Serum cholesterol Patient

 

trace

 

negative

 

139 mg/dL

 

185 mg/dL

 

4.8%

 

220 mg/dL Normal Range

 

negative

 

negative

 

< 140 mg/dL

 

<200 mg/dL

 

2.2 - 4.8%

 

<200 mg/dL The physician ordered an oral glucose tolerance test. After an overnight fast, a baseline blood sample

 

was drawn for both glucose and insulin levels. Then Donnatella drank 100 grams of glucose and blood

 

samples were drawn after 0.5, 1, 2, and 3 hours. The results of her tests are shown below. The shaded areas in the graphs indicate the normal range of expected values. This range is usually the

 

95% confidence interval, i.e., it includes 95% of the values from a healthy population.

 

Donnatella's physician also sent her to a clinical dietitian for an analysis of her diet. He recorded the

 

following data for a typical day with Donnatella:

 

Breakf ast: coff ee +cream/ sugar

 

Mid- AM:

 

coff ee +cream/ sugar

 

apple danish

 

Lunch:

 

Tuna salad sandwich w/ mayonnaise

 

small salad w/ oil/ vinegar dressing

 

4 large chocolate chip cookies

 

16 oz Pepsi-Cola

 

Afternoon: Doritos Cool-Ranch chips

 

16 oz Pepsi-Cola Supper: 12 Triscuits (eaten while cooking)

 

2 pork chops, f ried

 

?cup applesauce

 

1 cup mashed pot atoes w/ 1 T but ter

 

1 cup green beans w/ 1 T but ter

 

1 slice apple pie w/ 1 scoop vanilla ice cream

 

sweet tea

 

TV snacks: Mesquite-smoked BBQ potato chips

 

16 oz Pepsi-Cola BACKGROUND

 

Hormones play vital roles in the overall integration of metabolism. Insulin and glucagon, in particular,

 

have marked effects on the uptake, storage, and mobilization of fuels, and on related aspects of

 

metabolism.

 

Insulin is secreted by the -cells of the pancreas in response to

 

elevated plasma glucose. Insulin is a peptide hormone that

 

consists of two chains - an A chain of 21 amino acids and a B

 

chain of 30 amino acids - that are covalently joined by two

 

disulfide bonds. Insulin is synthesized as a single precursor

 

protein, preproinsulin, that contains about 55 amino acids not

 

present in the mature insulin molecule (see Figure below).

 

The preproinsulin molecule is synthesized in the cytoplasm,

 

after which it enters the endoplasmic reticulum, wherein the

 

signal peptide is removed to produce proinsulin; the proinsulin

 

moves to the Golgi apparatus and is packaged into secretory

 

granules. In these granules, prior to insulin secretion into the blood, the C-peptide is excised from the molecule by a proteolytic enzyme similar to trypsin. The mature insulin in these storage granules is

 

released into the circulation when these granules fuse with the cell membranes of the -cells of the

 

pancreas, in response to a rise in blood glucose concentration.

 

Processing of preproinsulin. Insulin is

 

synthesized as a 110 amino acid

 

precursor that undergoes a number of

 

proteolytic cleavages (arrows) to

 

produce the mature hormone. The

 

signal peptide enables the molecule

 

to enter the endoplasmic reticulum,

 

wherein the signal peptide is removed

 

and the various disulfide bonds are

 

formed. The resulting proinsulin

 

molecule is then sent to the Golgi

 

apparatus where it undergoes the

 

other cleavages to release the Cpeptide and the mature hormone

 

consisting of the A and B chains held

 

together by two disulfide bonds.

 

Figure reproduced with permission from St?y J. et al. Proc. Natl. Acad. Sci, USA

 

104: 15040-15044, 2007. Copyright (2007) National Academy of Sciences, U.S.A. In essence, insulin signals the fed state. It stimulates the storage of fuels and inhibits catabolic

 

processes such as breakdown of glycogen and fats. Insulin is the only hormone that lowers the

 

circulating glucose level. Circulating insulin binds to insulin receptors on cell surfaces of target cells

 

(see diagram below) and increases glucose entry into muscle cells and adipose tissue. Insulin

 

stimulates glucose uptake by increasing the number of glucose transporters present on the cell

 

membranes of target cells. There is an intracellular second messenger (IRS) involved in transducing

 

the signal resulting from insulin binding into an actual increase in glucose transporters present at the

 

cell surface.

 

The glucose transporters are proteins that span the cell membrane and transport glucose into the cell

 

(passive carrier-mediated uniporter transport). They are synthesized by insulin-responsive cells and

 

stored in a pool of intracellular membrane vesicles. When insulin binds to its receptor, these vesicles

 

move to the cell membrane and fuse with it, incorporating the glucose transporters into the cell

 

membrane. The effect of vesicle fusion is to increase the number of glucose transporters that are

 

present on the cell membrane, thereby increasing glucose uptake. When insulin no longer occupies the

 

insulin receptor, this process is reversed; glucose transporters are recycled back into vesicles that

 

return to the intracellular pool and are again available for fusion to the cell membrane the next time

 

glucose (and insulin) come along. This sequence of events occurs every time one eats a meal.

 

The adequate secretion of insulin by the pancreas and its unimpeded binding to the insulin receptor

 

are obligatory for the regulation of plasma glucose levels. In a normal individual, about half of the

 

ingested glucose in converted to energy through the glycolytic/TCA cycle, and about half is stored as fat

 

(fatty acids as triglycerides) and glycogen. In the absence of insulin, glycolysis decreases and

 

glycogenesis and lipogenesis are impeded. In fact, only about 5% of ingested glucose is converted to fat

 

in insulin-deficient diabetics. Insulin increases glucose uptake in skeletal muscle and adipose tissue by increasing the number of

 

glucose transporters in the cell membrane. Insulin alters the following metabolic pathways:

 

1) enhances the conversion of glucose to glycogen in liver and muscle

 

2) promotes peripheral uptake and utilization of glucose in muscle and adipose cells

 

3) inhibits lipolysis and enhances fatty acid and triglyceride synthesis in adipose cells

 

4) stimulates synthesis of amino acids from pyruvate in most cells

 

Hyperglycemia and glucose intolerance are common

 

manifestations of several types of hormonal

 

imbalances, the most common of which is diabetes

 

mellitus. For more information, look on the web at

 

www.diabetes.org. This disease is the seventh leading

 

cause of death in the USA, is responsible for 12% of all

 

new cases of blindness per year, and is involved in 25%

 

of all cases of end-stage renal disease. There are two

 

major types of diabetes mellitus.

 

Diabetes mellitus is a serious and extremely complex

 

disease in which the fundamental disorder is impaired

 

carbohydrate metabolism, arising secondary to

 

problems with insulin production and/or proper

 

utilization. It is typically characterized by

 

hyperglycemia and glucosuria. However, when

 

carbohydrate metabolism becomes seriously deranged,

 

abnormalities in the metabolism of proteins and lipids

 

also occur. Thus, diabetes mellitus may involve all of

 

the major metabolic pathways in an afflicted individual, a fact that greatly complicates the course and management of the disease. For example, severe

 

disturbances in lipid metabolism in the diabetic patient may result in ketoacidosis, coma, and death.

 

Type I diabetes (often called Insulin-Dependent Diabetes Mellitus; IDDM) is due to a complete absence

 

of insulin that results from an autoimmune destruction of the -cells in the pancreas. Replacement

 

therapy with daily insulin injections or pancreatic transplants is an absolute necessity. In the absence

 

of insulin, various metabolic pathways are altered and lead to the following abnormalities:

 

1)

 

2)

 

3)

 

4) hyperglycemia

 

glucosuria

 

ketosis and ketoacidosis (positive tests for ketones in blood and urine)

 

excretion of large amounts of water Prompt and continued therapy with insulin saves the lives of nearly all Type I diabetics, but many

 

develop serious complications within 10-15 years. The end stages may be one or more of the following:

 

stroke, myocardial infarction, loss of eyesight, renal failure, or neurologic defects. The periodic or

 

prolonged occurrence of hyperglycemia is believed to be partially responsible for some of these

 

complications. Glucose slowly forms an addition product with some proteins in a nonenzymatic

 

reaction by condensing with an exposed amino group to form a ketoamine (the reaction is called the

 

Maillard reaction after the French chemist who first described it; it is the same reaction that causes the

 

crust of baked bread to turn brown). The altered proteins have decreased functions, and these

 

disturbances probably play a role in the complications that develop.

 

The most studied glycosylated protein is glycosylated hemoglobin (HbA1C or just A1C). During the

 

120-day lifetime of an erythrocyte (red blood cell), glucose and reacts non-enzymatically with an amino group of the -chains of hemoglobin to form stable glycosylated hemoglobin. The reaction is

 

substrate-driven, so the reaction rate varies directly with the blood glucose concentration. Thus, the

 

concentration of glycosylated hemoglobin at any given time reveals the overall time-weighted

 

average concentration of blood glucose over the past four months. In normal individuals, glycosylated

 

hemoglobin comprises from 2-6% of the total, with an average of about 4.5%. It may rise as high as 1520% in diabetics whose hyperglycemia is difficult to control.

 

Type II Diabetes (formerly called Non-Insulin-dependent diabetes mellitus; NIDDM) is an initially milder

 

form of diabetes characterized by adult onset, functional pancreatic -cells, and insulin resistance (an

 

insufficient peripheral response to a given concentration of plasma insulin). The pancreas will continue

 

to secrete more insulin in an attempt to bring down blood glucose levels. Thus, insulin resistance can

 

exist without diabetes as long as the pancreas can secrete enough extra insulin to allow the glucose

 

transporters to do their job and keep plasma glucose levels within normal limits. However, when the

 

capacity of the pancreas for insulin release reaches its limit, diabetes will result. Note that although

 

Type II diabetes is generally thought of as a ?milder? form of diabetes, it is far more significant in terms

 

medical complications, costs to society, and deaths (see below).

 

The underlying cause of this insulin resistance is not fully understood, but there is a definite link to

 

obesity. Insulin resistance is present in most obese people, only some of whom will go on to actually

 

develop Type II diabetes. About 27% of adults are obese and/or insulin resistant to some degree. Each

 

year, between 1 and 5% of insulin resistant people will develop Type II diabetes. Of the 6% of

 

Americans who have Type II diabetes, 80% are obese. Genetics also plays an important role. With one

 

affected parent, there is a 25-30% chance of developing Type II diabetes. The concordance in

 

monozygotic twins is virtually 100%. Mexican-Americans are at an increased risk. NIDDM accounts for about 90% of all cases of diabetes mellitus. Reducing the weight of obese subjects can often control

 

it. The most widely prescribed drug for treatment of Type II diabetes is metformin (Glucophage),

 

which inhibits glucose production (gluconeogenesis) by the liver and also increases the tissues?

 

sensitivity to insulin. The sulfonylureas stimulate the pancreas to produce and release more insulin.

 

They include glipizide (Glucotrol), glyburide (Diabeta), and tolbutamide.

 

Type II diabetes is a major health

 

care concern, with enormous

 

economic impact. Economic costs

 

related to diabetes are well over

 

$100 billion/year, and it accounts for

 

about one-fifth of all personal health

 

care expenditures in the US.

 

Gestational diabetes (~4% of all pregnancies) results when placental hormones induce temporary

 

insulin resistance. It usually affects the mother in late pregnancy, after the fetus is largely developed

 

but before it is finished growing. Untreated, gestational diabetes results in macrosomia (fat baby),

 

which is associated with numerous potential health problems. Treatment involves special diets and an

 

exercise regimen; supplemental insulin is sometimes required.

 

Table 3. Characteristics of Diabetes

 

Characteristics

 

Age of Onset

 

% Total cases

 

Ketosis

 

Body weight

 

Insulin resistance

 

Endogenous insulin

 

Treatment w/ insulin Type I

 

(IDDM) Type II

 

(NIDDM) juvenile onset*

 

(usually <30 yrs)

 

5 - 10%

 

common

 

non-obese

 

absent

 

severe deficiency

 

always necessary adult onset*

 

(usually >40 yrs)

 

90 ? 95%

 

uncommon

 

50-90% are obese

 

present

 

variable ( to absent)

 

usually not necessary * - usually Most important criteria for diagnosis:

 

Hyperglycemia*

 

low arterial pH

 

ketonemia

 

low total CO2 content in blood

 

glucosuria

 

polyuria

 

ketonuria

 

polydipsia

 

* (= venous plasma glucose ? 140 mg/dl, or 7.8 mM)

 

The most common precipitating causes of diabetic ketoacidosis are:

 

1. omission or reduction of insulin in the previously diagnosed diabetic

 

2. previously undiagnosed diabetes complicated or precipitated by a condition of stress (bacterial

 

infection, pregnancy, etc.). QUESTIONS FOR GROUP DISCUSSION

 

1. Examine the laboratory data for Case I. List all the abnormal values and arrive at a

 

biochemical explanation for why each of these values is abnormal.

 

2. Why is glycosylated hemoglobin (HbA1c) level elevated in Case I? Why is this parameter useful

 

in monitoring diabetes and its treatment, i.e., what does it tell you?

 

Serum albumin is also easily glycosylated. It has an average lifetime in the circulation of about 25

 

days. In view of what you know about glycosylated hemoglobin and the life-span of erythrocytes

 

that contain it, how would information you get from monitoring glycosylated albumin levels differ

 

from that derived from glycosylated hemoglobin levels?

 

3. Four major abnormalities are listed on page 6 as being characteristic of Type I diabetes. For each

 

abnormality, explain why and how these abnormalities develop. You may need to use your lecture

 

slides from carbohydrate metabolism, or consult a biochemistry textbook or online source.

 

4. Consider Donnatella in Case II. Examine her lab data, the oral glucose tolerance test results, and her

 

insulin levels during this test. Is Donnatella diabetic? Does she have a problem with insulin

 

production and/or secretion? Is she insulin-resistant?

 

5. Examine Donnatella's diet. What might you suggest to her to improve her diet and her overall

 

physical condition?

 

Two months after being seen at the clinic, Donnatella returned for additional tests. She heeded

 

your advice, she lost 15 pounds, and she had been exercising regularly. Results of her OGTT and

 

insulin levels are given below. 6. Is Donnatella diabetic? Does she still have any problems or abnormalities? If so, what are they?

 

What might you expect her glycosylated hemoglobin levels to be on her return visit? Why?

 

What to include in your report:

 

1. An introductory paragraph, including a brief discussion of the role of insulin in normal metabolism as

 

well as abnormalities associated with Type I and II diabetes mellitus.

 

2. All of the answers to the group discussion questions.

 


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