DIABETES CASE STUDIES

Oral Agents There are seven classes of oral agents and they

have different mechanisms of action. Four of the classes are secretagogues: First and second generation sulfonylureas, meglitinide, and d-Phenylalanine. Two of the classes are insulin sensitizers: biguanides and thiazolidinediones. The α-glucosidase inhibitor class delays carbohydrate absorption from the gut. Combination drug therapy can have additive effects.

THE SECRETAGOGUES

All secretagogues allow the pancreas β-cells to secrete insulin in response to a glucose challenge. They are useful in patients with insulin deficiency.

Common side effects include hypoglycemia, weight gain, mild gastrointestinal complaints, and rarely skin reactions, photosensitivity, and cholestatic hepatitis. Secretagogues are contraindicated in pregnancy, and used with caution in patients with liver disease. They also should be used with caution in renal disease (except for repaglinide and nateglinide which don’t have renal dosage requirements).

There are four classes of secretagogues: first and second generation sulfonylureas, meglitinides, and d-Phenylalanine derivatives. Each secretagogue class works a little different.

THE INSULIN SENSITIZERS

Both classes of insulin sensitizers, biguanides and thiazolidinediones, are being researched as possible therapies that delay type 2 diabetes in patients with insulin resistance, glucose intolerance (pre-diabetes), or have high risk for diabetes. These drugs are used in patients with polycystic ovarian syndrome which carries a component of insulin resistance.

CARBOHYDRATE ABSORPTION DELAY AGENTS

Alpha-glucosidase inhibitors Alpha-glucosidase inhibitors delay disaccharide and

complex carbohydrate absorption in the small intestine and allow it to occur instead in the large intestine and colon. This mechanism allows improvement of glucose control. It does not have the same delay effect on lactose.

This class is excellent for patients with high 2 hour post meal hyperglycemia, and can be used in people with both insulin resistance and deficiency. They must be used with each meal to be effective. They reduce A1C by 0.5 – 1% when combined with other oral agents or insulin. Two α-glucosidase drugs are approved for use in the United States: acarbose and miglitol.

TYPE TWO DIABETES

When you have type 2 diabetes, your body is resistant to the effects of insulin or your body produces some, but not enough, insulin to maintain a normal glucose level. Left uncontrolled, the consequences of type 2 diabetes can be life-threatening.

SYMPTOMS OF TYPE II DM Increased thirst and frequent urination. As excess sugar

builds up in your bloodstream, fluid is pulled from your tissues. This may leave you thirsty. As a result, you may drink — and urinate — more than usual.

Extreme hunger. Without enough insulin to move sugar into your cells, your muscles and organs become depleted of energy. This triggers intense hunger that may persist even after you eat.

Weight loss. Despite eating more than usual to relieve your constant hunger, you may lose weight. Without the energy sugar supplies, your muscle tissues and fat stores may simply shrink.

Fatigue. If your cells are deprived of sugar, you may become tired and irritable.

Blurred vision. If your blood sugar level is too high, fluid may be pulled from your tissues — including the lenses of your eyes. This may affect your ability to focus.

Slow-healing sores or frequent infections. Type 2 diabetes affects your ability to heal and fight infections. Bladder and vaginal infections can be a particular problem for women.

CAUSES

To understand type 2 diabetes, first you must understand how glucose is normally processed in the body.

The hormone insulin comes from the pancreas. When you eat, your pancreas secretes insulin into your bloodstream. As insulin circulates, it acts like a key that allows sugar to enter your cells. Insulin lowers the amount of sugar in your bloodstream. As your blood sugar level drops, so does the secretion of insulin from your pancreas.

CAUSES

Your liver acts as a glucose storage and manufacturing center. When your insulin levels are low — when you haven't eaten in a while, for example — your liver releases the stored glucose to keep your glucose level within a normal range.

In type 2 diabetes, this process works improperly. Instead of moving into your cells, sugar builds up in your bloodstream. This occurs when your pancreas doesn't make enough insulin or your cells become resistant to the action of insulin. Exactly why this happens is uncertain, although excess fat — especially abdominal fat — and inactivity seem to be important factors.

RISK FACTORS

Researchers don't fully understand why some people develop type 2 diabetes and others don't. It's clear that certain factors increase the risk, however, including:

Weight. Being overweight is a primary risk factor for type 2 diabetes. The more fatty tissue you have, the more resistant your cells become to insulin.

RISK FACTORS

Inactivity. The less active you are, the greater your risk of type 2 diabetes. Physical activity helps you control your weight, uses up glucose as energy and makes your cells more sensitive to insulin.

Family history. The risk of type 2 diabetes increases if a parent or sibling has type 2 diabetes.

Race. Although it's unclear why, people of certain races — including blacks, Hispanics, American Indians and Asian Americans — are more likely to develop type 2 diabetes.

Age. The risk of type 2 diabetes increases as you get older, especially after age 45. Often, that's because people tend to exercise less, lose muscle mass and gain weight as they age. But type 2 diabetes is increasing dramatically among children, adolescents and younger adults.

Prediabetes. Prediabetes is a condition in which your blood sugar level is higher than normal, but not high enough to be classified as type 2 diabetes. Left untreated, prediabetes often progresses to type 2 diabetes.

Gestational diabetes. If you developed gestational diabetes when you were pregnant, your risk of developing type 2 diabetes later increases. If you gave birth to a baby weighing more than 9 pounds, you're also at risk of type 2 diabetes.

MECHANISM?? Your body manufactures insulin after a meal as a way

to alert cells that higher levels of glucose are coming soon. The insulin signal attaches to special receptors on the cell surfaces, which respond by causing the cell to turn on its glucose-transporting machinery.

Individuals who suffer from type 2 diabetes have normal or even elevated levels of insulin in their blood, and normal insulin receptors, but for some reason the binding of insulin to their cell receptors does not turn on the glucose-transporting machinery like it is supposed to do. For 30 years researchers have been trying to figure out why not.

LATEST SCIENTIFIC STUDIES……

How does insulin act to turn on a normal cell’s glucose transporting machinery? Proteins called IRS proteins (the names refer not to taxes, but to insulin receptor substrate) snuggle up against the insulin receptor inside the cell. When insulin attaches to the receptor protein, the receptor responds by adding a chemical called a phosphate group onto the IRS molecules. Like being touched with a red hot poker, this galvanizes the IRS molecules into action. Dashing about, they activate a variety of processes, including an enzyme that turns on the glucose transporter machinery.

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When the IRS genes are deliberately taken out of action in so-called “knockout” mice, type 2 diabetes results. Are defects in the genes for IRS proteins responsible for type 2 diabetes? Probably not. When researchers look for IRS gene mutations in inherited type 2 diabetics, they don’t find them. The IRS genes are normal.

This suggest that in type 2 diabetes something is interfering with the action of the IRS proteins. What might it be? An estimated 80% of those who develop type 2 diabetes are obese, a tantalizing clue.

What is the link between diabetes and obesity? Research reported this month suggests an answer to this key question. A team of scientists at the University of Pennsylvania School of medicine led by Michael Lazar had been investigating why a class of drugs called thiazolidinediones (TZDs) helped combat diabetes. They found that TZDs cause the body’s cells to use insulin more effectively, and this suggested to them that the TZD drug might be targeting a hormone.

Lazar’s team set out to see if they could find such a hormone in mice. In search of a clue, they started by looking to see which mouse genes were activated or deactivated by TZD. Several were. Examining them, they were able to zero in on the hormone they sought. Dubbed resistin, the hormone is produced by fat cells and prompts tissues to resist insulin. The same resistin gene is present in humans, too. Lazar speculates that resistin evolved to help the body deal with periods of famine.

Mice given resistin by the researchers lost much of their ability to take up blood sugar. When given a drug that lowers resistin levels, these mice recovered the lost glucose-transporting ability.

Researchers don’t yet know how resistin acts to lower insulin sensitivity, although blocking the action of IRS proteins seems a likely possibility.

Importantly, dramatically high levels of the hormone were found in mice obese from over-eating. Finding this sort of result is like ringing a dinner bell to diabetes researchers. If obesity is causing high resistin levels in humans, leading to type 2 diabetes, then resistin-lowering drugs might offer a diabetes cure

The body of a type II diabetic, due to an overproduction of insulin, can no longer produce the correct amount to maintain healthy blood sugar levels and begins to develop a resistance to insulin. Usually, this diagnosis comes after 40 years of age, but the condition is now increasingly found in children. Since 1968, obesity in American children has doubled, and today, approximately 25% of American children are obese. This increase in obesity has been directly linked to the rise in type II diabetes in both children and adults.

Studies have shown that an increase in abdominal fat is linked to glucose intolerance, as well as to overeating and general obesity. A body mass index (BMI) of over 40 has been linked to a higher chance of developing diabetes. According to the Centers for Disease Control and Prevention (CDC), a healthy BMI ranges from 18.5 to 24.9. Obese individuals often have diets high in carbohydrates, starches and sugars, and low in protein and good fats. The way in which these foods are digested is related to how the body processes sugar.

Since humans and mice are genetically very similar, the researchers of DIfE use the mouse model to identify genes involved in the development of overweight and diabetes. If an “overweight gene“ has been discovered which plays a role in both species, then the researchers can investigate its function and the basic molecular mechanisms in animal models under controlled conditions. Such studies often cannot be carried out in humans for ethical as well as practical reasons. The results from the animal model studies can then be used to develop new medications for treatment of obesity and diabetes.

Seven base pairs are missing in the mutated Tbc1d1 gene of the Swiss Jim Lambert strain. These changes lead to the synthesis of a shortened Tbc1d1 protein molecule and, most likely, loss of enzyme activity. The Tbc1d1 protein molecule is located mainly in skeletal muscle. Researchers have found smaller amounts in heart, pancreas, intestine, kidney, and hypothalamus. It is not found in fatty tissue or liver.

INSULIN RESISTANCE

This means that as the blood sugars are chronically elevated, and the insulin levels are rising, the cells build a shield or wall around themselves to slow down this influx of excess sugar. Insulin resistance is a protective or adaptive response, it is the best the body can do to protect the cells from too much glucose. But as time goes on the sugar in the blood increases, more insulin is made by the pancreas to deal with this elevated sugar and the cells resist this sugar influx by becoming insulin resistant, in a sense by shutting the gates. This leads to the curious situation in which blood sugar levels are high but cellular sugar levels are low. The body perceives this as low blood sugar. The patient has low energy and feels hungry so he eats more, and the vicious cycle is under way.

INSULIN RESISTANCE

Having a chronically elevated insulin level is detrimental for many other reasons. Not only do high insulin levels cause obesity (insulin tells your body to store fat), but they also signal that fluid should be retained, leading to edema and hypertension. Chronic high insulin provokes plaque development inside the arteries and also suppresses growth hormone needed for the regeneration of the tissues and many other physiological responses.

CASE ONE

72 yo CM woke up this morning with weakness in his left leg. He noted difficulty in lifting up his left foot from the floor. He has no other complaints.

The patient has bought a computer recently and has been browsing the web, sitting with legs crossed for prolonged periods.

PMH:DM 2, HTN

Medications:Lisinopril, Cardizem, Insulin 70/30

Physical examination:VSSWD/WNExtremities: no c/c/e5/5 RLE; 3/5 left foot dorsiflexion; sensation is intact

DIAGNOSIS?

5 = OK4 = Resists movement3 = Gravity overcome2 = No gravity overcome1 = Flicker of movement0 = No movement at all

Peroneal palsy or foot drop

The most likely reason is mechanical trauma to the peroneal nerve at the fibular head. The trauma is due to the body position of sitting for prolonged periods with crossed legs. Peroneal palsy is more common in diabetic patients because they may already have underlying subclinical ischemia which is exacerbated by the mechanical trauma.

CASE TWO

A 37 year-old male was seen in the emergency room with polyuria, thirst and weight loss for one month and vomiting for 3 days. His blood glucose was 13.6mmol / L, urine ketone was positive (+++), with low insulin secretion.

He was diagnosed as type2 diabetes and ketosis.

PATIENT THREE

A 32 year-old male with a history of polyuria, thirsty and weight loss for 5 months was admitted to BCDH. Blood tests showed hyperglycemia (23.7mmmol/L) and urine ketone positive (++).

Treatment given included insulin by pump, then insulin injections subcutaneously and drugs for to improve microcirculation, insulin receptor activity and preservation of B cell function.

CASE NUMBER FOUR

Mrs. Gomez is a 39 year old Mexican American mother of two. She visits her doctor complaining of fatigue and frequent urination (polyuria) and also reports blurry vision and tingling in her feet. She has a family history of diabetes and both of her children weighed more than nine pounds at birth. She speaks limited English.

CASE FOUR

An initial physical examination reveals the following information:

Height = 5' 4" Weight = 200 pounds BMI = 34.2 Waist Circumference = 36 inches Blood Pressure = 146/88 Random Blood Glucose = 228 mg/dL Microaneurisms (retinal exam) Normal monofilament test

MS GOMEZ

Laboratory Values (Fasting) PG (random) 185 mg/dL A1C 9.2% LDL-C 158 mg/dL HDL-C 42 mg/dL TG 310 mg/dL Microalbumin 45 mg/g creatinine Normal creatinine and liver profile

CASE GOMEZ

Fasting Plasma Glucose - Level is above normal (normal <100 mg/dL, type 2 diabetes ≥126 mg/dL)

HDL, LDL, and TG are all abnormal for type 2 diabetes. As is often seen in type 2 diabetes, her HDL and triglycerides are

high. In addition, her LDL is significantly elevated, which is not typical for type 2 diabetes. All of these need to be addressed.

The patient has microalbumenuria, between 30 and 300 mg/g creatinine.

Percent A1C - Level is elevated and is 2% above target.6

For every 1% that the A1C exceeds 7%, the risk of mortality over 10 years is 10% from cardiovascular causes and 17% from cerebrovascular causes.7

Given her A1C level, this patient has a 54% increased risk of mortality (20% cardiovascular and 34% cerebrovascular).

DIAGNOSES

Mrs. Gomez is likely to have hypertension, Mrs. Gomez also has type 2 diabetes. She has a

random glucose >200 mg/dL along with polyurea. Pre-diabetes has been defined as a fasting glucose between 100mg/dL and 126mg/dL or a two hour post glucose challenge between 140 mg/dL and 200 mg/dL.2

Given this patient's history of having two children weighing more than 9 pounds at birth, it is likely she had gestational diabetes during her pregnancy

CASE FIVE

A 56-year-old type 1 diabetic male of 20 years duration, controlled on a twice daily 30/70 insulin regime, with a mean glycated haemoglobin of 7.6% (n.r. 5.0-6.2%) over the previous two years, complained of a gradual numbness and tingling in his right (dominant) hand over the previous six months. These sensory abnormalities were present in the medial part of the palm and medial one and a half digits. Examination confirmed diminished sensation to light touch and pin prick in this ulnar nerve distribution.

On further inspection, it was noted that there was a characteristic claw hand appearance (main-en-griffe) typical of ulnar nerve entrapment at the elbow. The fourth and fifth metacarpal phalangeal joints were hyper-extended with an inability to flex the distal interphalangeal joints and an inability to extend the interphalangeal joints (see figure 1). In addition, it was noted that there was moderate wasting of the inter-ossei muscles and abductor digiti minimi. The muscles of the thenar eminence were spared. There was no other disease e.g. cervical spondylosis, noted to cause small muscle wasting of the hand.

Background retinal changes were present on fundoscopy. The blood pressure was 130/80 mmHg. No microalbuminuria was detected. There were no clinical features of peripheral or autonomic neuropathy. There were no obvious macro-angiopathic complications with no previous history of heart disease, stroke or peripheral vascular problems.

ULNAR NERVE NEUROPATHY

Motor conduction velocities were measured in the upper arm, transsulcal (elbow) and forearm segments of the right and left ulnar nerves. There were normal conduction velocities on the left side but the findings in the right arm confirmed entrapment with the ulnar nerve compressed in the cubital tunnel formed by the two tendon heads of flexor carpi ulnaris which arch across between the humerus and the ulna. Surgical decompression was performed. The sensory features resolved after 3-4 weeks. The motor features of the ulnar nerve palsy were more slow to improve and after a further year the claw hand appearance was less marked and the inter-osseal muscles less wasted. The patient had full functional use of the hand at this stage.

DIABETES CASE STUDIES…MOWAH…..

M.G. is a 58 y/o white female who presents to her primary care physician with a complaint of “tired all the time.”

It’s been going on for several months, and she doesn’t report any concerns with nighttime sleep. She doesn’t note any new stress or other life changes, and denies depression or anxiety.

Alcohol consumption is limited to one to two drinks per week, and she quit smoking over 10 years ago.

Family history is notable for type 2 diabetes in an older sister; her mother had hypothyroidism and “heart disease.”

The patient also has high cholesterol that she has been trying to treat with “weight loss and exercise.”

She walks about 20 minutes three times weekly when the weather allows.

She has been treated for about five years for hypertension with hydrocholorthiazide.

  The pertinent findings on physical

exam: Height:5’4” Weight:212 lbs. BMI:36

BP:135/86 Heart/Lungs: Normal exam Abdomen: Obese and benign No

thyromegaly Vision and optic fundi: normal Feet: normal Remainder unremarkable

Risk factors for development of diabetes?

Her risk factors include hypertension, dyslipidemia (cholesterol disease), obesity, family history of type 2 diabetes, and cigarette smoking,

which is an independent risk factor for the development of type 2 diabetes.

What labs would you order for this patient? Typically, for a patient with this complaint and history,

type 2 diabetes would be considered. Anemia and hypothyroidism would be other

possibilities in a differential of common diagnosis. In this case, complete blood count and TSH were

normal. Other blood chemistries, including kidney and liver

function tests were normal. Casual blood glucose (random) was 210. She was brought back for a fasting glucose 2 days

later, which was 129.

Does this patient have diabetes? The answer is most likely. A casual blood glucose of >200 can be

used for diagnosis if the patient has classic symptoms of diabetes or hyperglycemia, such as polyuria, polydipsia, weight loss.

The patient does report fatigue, likely due to hyperglycemia. A fasting blood glucose value of >126 is also very suggestive.

Classically, this patient would need another fasting blood glucose value of >126 for diagnosis.

In this case, that was done one week later, and the patient’s fasting glucose was 138, giving her a diagnosis of type 2 diabetes.

An A1C was also drawn at that time, which was 7.6%. A1C is not yet recommended for diabetes diagnosis, although that could change in the future.

C.M. is a 27-year-old woman with type 1 diabetes diagnosed at age 14 when she presented with diabetic ketoacidosis.

Her initial insulin treatment was complicated by poor glycemic control, frequent hypoglycemia, and weight gain.

Two years ago, she developed hypertension, which was treated with hydrochlorthiazide, 25 mg daily.

At that time, she was noted to have nonproliferative diabetic retinopathy.

Blood urea nitrogen (BUN) was 23 mg/dl,

creatinine was 0.9 mg/dl, and dipstick urinalysis was negative for protein.

She now presents with accelerated hypertension (172/108 mmHg) and pitting edema of the legs to the level of the knees.

Urinalysis reveals 3+ protein and 2+ blood. Urine microscopic analysis reveals hyalin and red blood cell casts.

BUN is 37 mg/dl; creatinine is 1.5 mg/dl; and 24-h urine reveals 9.7 g of protein. Creatinine clearance is 58 ml/min. Total

cholesterol is 279 mg/dl.

Does C.M. have diabetic nephropathy? What diagnostic tests are indicated?

We believed that C.M. had type 1 diabetes with nonproliferative retinopathy, accelerated hypertension, and nephrotic syndrome.

Although the history of retinopathy and hypertension were consistent with the development of diabetic nephropathy, the urinary findings and rapid progression of renal insufficiency were inconsistent with diabetic nephropathy

and raised the specter of a second etiology of her renal disease.

On further testing, Westergren erythrocyte sedimentation rate was 81 mm/h,

urine immunoelectrophoresis was negative for Bence Jones protein,

and rheumatoid factor was negative, but antinuclear antibody was positive in a titer of

1:320 with a homogenous pattern. Anti-DNA was 5.1% (normal 0–7%).

C3 complement was low, C4 complement was normal, and CH 50 was at the lower limit of normal.

Renal biopsy demonstrated mixed proliferative and focal membranous glomerulonephritis consistent with lupus nephropathy.

In addition, changes were present suggestive of early diabetic glomerulosclerosis.

Approximately 40% of people with longstanding type 1 diabetes develop diabetic nephropathy. Essentially all patients with diabetic nephropathy have diabetic retinopathy detectable by dilated retinal examination.

In type 1 diabetes, diabetic nephropathy follows a predictable course from onset of diabetes to the onset of microalbuminuria to frank nephropathy to end-stage renal disease or death.

Microalbuminuria develops 10–14 years after onset of diabetes. Without treatment, clinical nephropathy follows within 5 years, and azotemia develops ∼5 years later.

Hypertension develops in association with microalbuminuria and progresses with diabetic nephropathy. In diabetic nephropathy, the urine sediment is bland. Red blood cells are usually absent, although they may be present with infection or in the rare instance of papillary necrosis. Red cell casts are absent.

Diabetic nephropathy is a diagnosis of exclusion.

In this case, accelerated hypertension, an active urinary sediment with both red cells and red cell casts, and the rapid onset of nephrotic syndrome with renal insufficiency is more consistent with glomerulonephritis mediated by immune mechanisms.

Thus, thorough testing for secondary causes of immune-mediated glomerulonephritis, including renal biopsy, were indicated to identify a second, more treatable, cause of renal disease.

Diabetic nephropathy or intercapillary glomerulonephritis, is a progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli.

It is characterized by nephrotic syndrome and diffuse glomerulosclerosis. It is due to longstanding diabetes mellitus, and is a prime indication for dialysis in many Western countries.

The earliest detectable change in the course of diabetic nephropathy is a thickening in the glomerulus.

At this stage, the kidney may start allowing more serum albumin (plasma protein) than normal in the urine (albuminuria), and this can be detected by tests for albumin.

This stage is called "microalbuminuria". As diabetic nephropathy progresses, increasing

numbers of glomeruli are destroyed by nodular glomerulosclerosis.

Now the amounts of albumin being excreted in the urine increases, and may be detected by ordinary urinalysis techniques.

At this stage, a kidney biopsy clearly shows diabetic nephropathy.

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