THE ENDOCRINE SYSTEM

 

A.        Physiology

 

            1.         Structure and function

 

                        a.         Composed of various glands located throughout the body. 

 

b.         These glands are capable of synthesizing and releasing special chemical messengers called hormones.

 

                        c.         Glands include:

                                    (1)        Hypothalamus

                                    (2)        Pituitary

                                    (3)        Pineal gland

                                    (4)        Thyroid

                                    (5)        Parathyroids

                                    (6)        Thymus

                                    (7)        Pancreas (islets)

                                    (8)        Adrenals

                                    (9)        Ovaries/testes

 

                        d.         Functions include:

(1)        differentiation of the reproductive system and CNS in the developing fetus

 

(2)        stimulation of sequential growth and development during childhood and adolescence

 

(3)        coordination of the male and female reproductive systems, which makes sexual reproduction possible

 

(4)        maintenance of an optimal internal environment throughout the lifespan

 

(5)        initiation of corrective and adaptive responses when emergency demands occur

 

            2.         Hormonal regulation mechanisms

 

a.         Endocrine glands respond to specific signals by synthesizing and releasing hormones into the circulation.

 

                        b.         Hormones have specific rates and patterns of secretion.

                                    (1)        diurnal patterns

                                    (2)        pulsatile and cyclic patterns

(3)        patterns that depend on levels of circulating substrates (e.g., calcium, sodium, potassium, or the hormones themselves)

 

c.         Hormones operate within feedback systems, either positive or negative, to maintain an optimal internal environment

 

d.         Hormones affect only cells with appropriate receptors and then act on these cells to initiate specific cell functions or activities

 

e.         Hormones are constantly excreted by the kidneys or deactivated by the liver or by other cellular mechanisms

 

Neuroendocrine = the endocrine and nervous systems work together to regulate responses to the internal and external environment. 

•     Both secrete regulatory substances into the bloodstream

•     Both can generate electrical potentials

 

Hypothalamus --> pituitary:

 

Pituitary:

- anterior lobe:  remnant embryologically of throat, so GI tissue, not endocrine; = adenohypophysis

- middle lobe:  only present in lower forms of animals

- posterior lobe:  = neurohypophysis

 

To send messages, there is blood supply which connect the anterior and posterior lobes = hypophyseal portal system.

 

The hypothalamus influences the pituitary by releasing factors and inhibiting factors.

 

The pituitary subsequently releases specific hormones to influence target organs to produce hormones that influence energy production, the stress response, fluid and electrolyte balance, growth and reproduction, and the development of personality.

 

Example:

 

            Stress (“fight or flight” response = “automatic” functioning thru limbic system)

                ¯     

            Hypothalamus

                ¯

            Corticotropic releasing factor (“-tropic” = affinity)

                ¯

            Anterior pituitary

                ¯

            ACTH  (works 2-6 am)

                ¯     

            Adrenal gland

                ¯

            Cortisol (highest at 8 am) (slower response-type stress hormone; makes sugar for    energy so cortisol = glucocorticoid)

 

“diabetic dawn phenomenon” = Cortisol --> increased BS at early morning (BS may be 300-500); may need noc dose of NPH to cover.

            Tx:  BIDS (bedtime insulin, daytime sulfonylureas)

 

Negative feedback:  when don’t need end hormone, tells producers to shut off.

 

            When you have enough of the end-product, in this case, cortisol, a negative feedback system turns off the adrenal gland production of cortisol, the pituitary gland production of ACTH, and the hypothalamic production of C-RF.

 

            This turns off the HPA (hypothalamic-pituitary-adrenal) axis.

 

            The same thing occurs when we give cortisol to our patients at high doses for long periods of time--we shut down the HPA axis.

 

Prednisone = “end product”, so tells HPA axis to shut off. 

 

The HPA axis cannot turn back on suddenly, therefore we have to taper the drugs so that the patient’s own system can turn back on.

 

•     Taper high-dose (> 5 mg/day) Prednisone

•     If not, patient goes into adrenal crisis (hypocortical crisis) and dies.

•     After tapered, for 1 year need to carry Prednisone to take at times of high stress (such as death in family)

 

So, generally, the format/process  is:

 

            Stimulus

                ¯

            Hypothalamus

                ¯

            Releasing factors

                ¯

            Anterior pituitary

                ¯

            Trophic hormones

                ¯

            Target organ

                ¯

            Hormone

                ¯

            Physiologic Response

 

When something goes wrong with too much or too little of the end product, such as cortisol in the earlier example, you have to think about where in the axis this might have happened.

 

For example, a patient is admitted with all of the signs and symptoms of too much cortisol (Cushing’s syndrome).  Where could the problem be?

 

            1.         Check the target organ (adrenal gland) = Cushing’s syndrome

 

It could be a tumor of the adrenal gland producing too much cortisol.  This would be primary hypercortisolism.  It is a problem with the primary organ.

 

            2.         Check the pituitary (Cushing’s disease)

 

If it is a tumor from the anterior pituitary, producing too much ACTH, which in turn is overstimulating the adrenal gland, we call it secondary hypercortisolism, or Cushing’s disease.

 

            3.         Check the hypothalamus (also = Cushing’s syndrome)

 

Our last possibility is a tumor or problem with the hypothalamus which would be referred to as tertiary hypercortisolism.

 

            4.         Check medications

 

5.         Check for ectopic hormone production (oat cell carcinoma of the lung is a primitive cell type which can produce hormones)

 

Another example:

 

            Hypothalamus

                ¯

            Thyrotropic releasing factor

                ¯

            Anterior pituitary

                ¯

            TSH

                ¯

            thyroid

                ¯

            T3, T4

 

If problem:      Check thyroid ---> Primary hypothyroidism

 

                        Check pituitary --->  Secondary hypothyroidism

 

Note:   Increased TSH in Primary hypothyroidism

 

            No TSH, T3, T4 in Secondary hypothyroidism

 

(* Depression is one of the presentations of hypothyroidism.  Antidepressants, such as Zoloft, won’t work without Synthroid.  Early on, the TSH may not be elevated yet.)

 

Primary ovarian hypofunction = menopause

 

Negative feedback:

 

            Pituitary  (Benign tumor here causes increased ACTH and increased cortisol =

            ¯                      secondary hypercortisolim or Cushing’s disease

            ¯

            ACTH

            ¯                                  Negative

            Adrenal gland             feedback        

            ¯                                  ­                     

            If increased serum cortisol                 

                                               

 

Adrenal gland: 

10% benign tumors produce hormones of origin

8% malignant tumors (can produce cortisol, unlike most malignant tumors, which don’t)

 

Anterior pituitary - dopamine is the neurotransmitter which influences hormones to be released (inversely)

 

                        Increase dopamine, decrease hormone release

                        Block dopamine, increase hormone release

 

When thinking about clinical problems with hormones, it is fairly simple...you either have too much of the hormone or you have too little (“hyper” or “hypo”).

 

HORMONES OF THE POSTERIOR PITUITARY

 

ADH (vasopressin) - antidiuretic; conserves free water (no electrolytes) and vasoconstricts to maintain blood pressure

 

Too little ADH = diabetes insipidus (water can’t come back in; results in the inability to conserve water with the signs and symptoms of severe polyuria, polydipsia, and low specific gravity)

                        Causes:  head trauma, meningitis, neurosurgery, tumors

           

Too much ADH = syndrome of inappropriate ADH (SIADH) (persistent release of ADH unrelated to plasma osmolarity; results in excessive reabsorption of free water with subsequent hemodilution, hyponatremia, and the inability to excrete a dilute urine.

Causes:  oat cell carcinoma of lung, head trauma, meningitis (assume SIADH in first 24 hrs, so don’t overdo fluids - restrict somewhat until sodium is OK), surgery/anesthesia, meds (Demerol, Tylenol --> decreased sodium)  Note:  Sodium < 120 ---> tonic-clonic seizures)

 

Oxytocin: 

            - milk letdown response

            - increases prostaglandin production ---> uterine contractions

 

HORMONES OF THE ANTERIOR PITUITARY

 

ACTH (adrenocorticotropic hormone):

            Stimulates the adrenal cortex to produce cortisol (cortisol is the hormone of stress and energy production)

            Most ACTH is produced at night, therefore cortisol levels are highest in the morning.

 

What are the clinical manifestations of an individual who has too much cortisol? 

            - Remember, this can be primary (adrenal), secondary (pituitary), or tertiary (hypothalamus) or pharmacologic (Prednisone).

            - Remember, ACTH = catabolic hormone (breakdown)

           

•     protein breakdown in the skin and skeletal muscle (this protein is turned into glucose = gluconeogenesis)

•     skin thins out, so see capillary layer ---> purple striae

•     glycogen breakdown into glucose ---> hyperglycemia (secondary diabetes; 15% need insulin)

•     has aldosterone properties ---> retain sodium and water ---> hypertension and decreases potassium ---> leg weakness

•     inhibits segs = anti-inflammatory

•     inhibits lymphs = immunosuppressive

•     changes in fat distribution - moves fat to center (syntrepidal obesity = face, stomach, buffalo hump) ( = “olive with legs and arms”)

•     increased gastric acid secretion; decreased gastric mucus production (predisposes doesn’t cause to have ulcers)

•     appetite stimulant

•     moves calcium out of bone (---> osteoporosis) (If on long-term Prednisone, as with lupus, work on bones by increasing calcium intake, exercising)

•     euphoric initially ---> dysphoric (depression)

 

So, in US, chronic stress leads to:

•     increased ulcer disease

•     increased HTN

•     increased obesity

•     increased osteoporosis

•     increased depression

 

Too little cortisol:

Causes:  inadequate stimulation of the adrenal glands by ACTH or because of a primary inability of the adrenals to produce and secrete the adrenal cortical hormones

           

Primary adrenal insufficiency = Addison disease (caused by autoimmune mechanisms, more common in women)

 

Growth hormone:  anabolic (build up) hormone that stimulates somatic tissue growth via protein build-up in the tissues; also stimulates glucose production for energy to grow

 

            - now made from recombinant DNA

            - only produced at noc in Stage III and IV sleep

            - can cause BS problems in DM

            - stop growing at about age 22

 

            - Too little = dwarfism

            - Too much before the age of 22 = giantism

- Too much after the age of 22 = acromegaly (protruding jaw; deep voice from thickened voice box)

 

TSH (thyroid stimulating hormone)

            Stimulates the thyroid gland to produce T3, T4

 

FSH, LH:

            - stimulate egg and sperm production

            - stimulate estrogen and testosterone production

 

            Hypothalamus

                ¯

            Gonadotropic releasing hormone

                ¯

            Anterior Pituitary

                ¯

            FSH, LH

                ¯

            ovary (egg prep and estrogen production = follicular phase of menstruation)

                       

 

@ 6 months gestation = 3.5 million eggs/ovary; then atresia (ovarian dropout), so only 400,000 eggs at birth.  By age 30, 100,000 eggs left.  By age 50, 3 eggs left (can still get pregnant).

 

            Estrogen fluctuation ---> hot flash, acne, UTI, S/S of perimenopause)

                        Already losing calcium from bone (start low-dose BCP)

 

            If can’t use estrogen (smokers > 35 yrs. old), use progesterone.

            Can use Fosamax (1/2 dose 5 mg for prevention)

 

            Estrogen/FSH fluctuations continue for 3-5 years.

 

When estrogen starts to decrease, FSH will increase:

 

            FSH < 20        premenopausal

            FSH 20-30      perimenopausal  (about age 47-48)

            FSH > 30        postmenopausal

 

Follicular phase:  FSH increases right after period (first 12 days)...know what part of phase they’re in when checking FSH level.

 

synthetic FSH = Clomid, Pergonal (= fertility drugs)  (originally made from urine of postmenopausal nuns (high FSH levels) in Italy

 

Release 1 egg/month  up to age 35; 2-3 eggs/month after 35 y.o. (increases risk of twins/triplets)

 

incessant ovulation theory - with each ovulation, a egg bursts from ovary = wound ---> temperature and need for proliferation of epithelial cells in ovaries ---> increased risk of cancer (85% of ovarian cancer = epithelial)...so, increased risk of ovarian cancer with infertility drugs.

 

If ovarian cancer, usually within 6 years of menopause (age 50-60) when increased FSH is hitting on the proliferated cells.  (Helps:  estrogen replacement therapy decreases FSH; BCPs)

 

Sperm production:  takes 2 months to mature

            Sperm from 20 year old male takes 20-50 minutes to swim the 5” fallopian tube

(= us swimming 2,000 miles)

Sperm from 80 year old male takes 2 1/2 days.

            Males produce sperm until they die.

 

Prolactin

            - promotes lactation

            - emotions (after puberty F> M; before puberty F/M cry equally)

            - inhibits ovulation

            - normally inhibited by an inhibiting factor from the hypothalamus

 

            - Too much:

tumor (prolactinoma) --> too much prolactin --> galactorrhea, amenorrhea, loss of libido, headache in AM.  If tumor gets big enough, pushes up on optic chiasm --> bitemporal hemianopsia (tunnel vision = loss of peripheral vision)

 

(This is different from the loss of peripheral vision seen in the elderly where the eyeball shrinks back into the socket.)

 

 

HORMONES OF THE THYROID GLAND

 

The thyroid gland is under the influence of TSH from the anterior pituitary gland.

 

It stimulates the thyroid to produce T3, T4 which bind to TBG (thyroid-binding globulin).

            T3 is the active hormone

            T4 is converted to T3 in the tissues

            Once in the tissues, T3 influences all aspects of metabolism

 

Too much thyroid hormone = hyperthyroidism

Due to 1) toxic adenoma (George Bush had this), 2) Grave’s disease (Barbara Bush had this; exophthalmos), or 3) autoimmune disease in which the antibodies act as thyroid stimulating agents)

                       

S/S = increased metabolism in all tissues (wt. loss, increased pulse, diarrhea, smooth skin, hot, tired (haven’t slept), can get depressed.

                        In elderly:  fatigue, wt. loss, atrial fib.

 

SO:  In elderly with atrial fib:  if not alcoholic or history of rheumatic heart disease, think hyperthyroidism

 

Thyroid hormone - regulates the number of beta-1 receptors on the SA node

            increased thyroid hormone level, increased # receptors, increased pulse

            decreased thyroid hormone level, decreased # receptors, decreased pulse

 

Thyrotoxic crisis (storm) - pulse can get to 300

            Causes:  surgical manipulation, not taking medication

            ** Need to block beta-1 receptors

            IV propranolol to prevent failure

            Also febrile -- give antipyretic

                        Tylenol will decrease the temp

                        ASA will kill the patient (ASA knocks the thyroid hormone off the receptor sites ---> increased pulse ---> heart failure

 

                        If minimally hypothyroid, 2 aspirin/day may increase to OK level.

 

Too little thyroid hormone = hypothyroidism

·         Primary case is Hashimoto’s thyroiditis, an autoimmune disease in which the antibodies attack and destroy the thyroid gland

·         Results in decreased metabolism

·         Lab tests:  antithyroglobulin antibodies, antimicrosomal antibodies

·         Severe or long-standing hypothyroidism --> myxedema

 

There is evidence of an association between subclinical hypothyroidism and CV disease.  The impact of thyroid hormone on lipid levels is primarily mediated through T3-bound thyroid protein binding and activation of the promoter regions of the LDL receptor and HMG CoA-reductase genes, leading to a reduction in serum cholesterol levels.  Thus the decreased T3 seen in hypothyroidism may result in increased serum cholesterol.  Current data suggest that normalizing even modest TSH elevations may result in improvement in the lipid profile.  (According to Feld, S, & Dickey, RA, (2001) in “An Association Between Varying Degrees of Hypothyroidism and Hypercholesterolemia in Women: The Thyroid-Cholesterol Connection.”)

 

HORMONES OF THE PARATHYROID GLAND

 

PTH (parathyroid hormone):  removes calcium from the bone to maintain serum calcium (stimulates osteoclasts to break down bone)

            Calcium is responsible for inhibiting neuromuscular excitability and activity.

 

            Estrogen inhibits PTH.

           

            One mechanism of osteoporosis = unopposed PTH

 

Calcitonin (a thyroid hormone):  lowers serum calcium by opposing bone-resorbing effects of PTH, prostaglandins, and calciferols by inhibiting osteoclastic activity.

 

So:  PTH acts to increase the concentration of calcium in the blood, whereas calcitonin (a hormone produced by the parafollicular cells (C cells) of the thyroid gland) acts to decrease calcium concentration.

 

PTH acts to increase calcium concentration in the blood by acting upon parathyroid hormone receptor in 3 parts of the body:

 

1.         Bones—PTH enhances the release of calcium from the large reservoir contained in the bones.  Bone resorption is the normal destruction of bone by osteoclasts, which are indirectly stimulated by PTH. Stimulation is indirect since osteoclasts do not have a receptor for PTH; rather, PTH binds to osteoblasts, the cells responsible for creating bone. Binding stimulates osteoblasts to increase their expression of RANKL, which can bind to osteoclast precursors containing RANK, a receptor for RANKL. The binding of RANKL to RANK stimulates these precursors to fuse, forming new osteoclasts which ultimately enhances the resorption of bone.

 

2.         Kidney-- It enhances active reabsorption of calcium and magnesium from distal tubules and the thick ascending limb. As bone is degraded both calcium and phosphate are released. It also greatly increases the excretion of phosphate, with a net loss in plasma phosphate concentration. By increasing the calcium:phosphate ratio more calcium is therefore free in the circulation.

 

3.         Intestine via kidney—In enhances the absorption of calcium in the intestine by increasing the production of activated vitamin D.  Vitamin D activation occurs in the kidney.  PTH regulates the enzyme responsible for 25-hydroxy vitamin D, which converts vitamin D to its active form.

 

NOTE:  Testing for 25-OHD (25-hydroxy-vitamin D) is being done in association with diagnosis of osteoporosis.  If decreased, there is poor bone health.

 

Remember, secretion of PTH is regulated by the calcium level in the blood, NOT by the hypothalamus or pituitary hormones. 

If calcium level is low, parathyroid gland releases parathyroid hormone (PTH).  PTH stimulates osteoclasts to break down bone, which increases the calcium level in the blood.  Calcitonin can block this process, thus decreasing the calcium level.

 

Too little PTH:  (from surgical removal) = hypoparathyroidism

S/S:  tetany, Chvostek’s sign (face), Trouseau’s sign (most sensitive; carpal spasm, “OB’s hand”), laryngeal spasm, paresthesias around lips, mouth, nose, confused, irritable

 

Too much PTH: =  hyperparathyroidism  = “bone and stone disease”; osteomalacia (too much calcium loss) and kidney stones

 

Secondary hyperparathyroidism:  renal failure patient

Can’t excrete phosphorus, so PTH causes breakdown of bones so calcium   can bind with phosphorus

 

 

Calcium-PTH Relationship: 

Clinical Application in Evaluating Calcium Levels

 

Calcium

PTH

Interpretation

Normal

Normal

Calcium regulation system is functioning OK.

Low

High

The PTH is responding as it should.  Consider further investigation of the hypocalcemia by looking at vitamin D, phosphorus, and magnesium levels

Low

Normal

To Low

The PTH is not responding.  Hypoparathyroidism probable.

High

High

The parathyroid gland is producing inappropriate amounts of PTH.  Imaging studies needed to check for cause and severity of hyperparathyroidism.

High

Low

The calcium regulation system is working normally, but further investigation is need to check for non-parathyroid related reasons for the elevated calcium. 

 

 

HORMONES OF THE ADRENAL GLAND

 

OF CORTEX:

 

Cortisol (mentioned previously)

 

Androgens:

- secondary sex characteristics (pubic/axillary hair- keeps odor close to body)

- turned into weak form of estrogen (estrone) when in fat tissue (strong enough to keep bones and brain OK)...so, skinny (<140 lbs), elderly = osteoporosis, Alzheimer’s

           

But with too much fat - increased risk of breast and uterine cancer, heart disease, DM

 

Facial hair - with unopposed androgens

 

Women using estrogen vaginal cream:  don’t use as sexual lubricant (male absorbs it ---> feminizes ---> gynecomastia (also excess Vitamin E), shrinkage

 

Aldosterone:  conserves sodium and water from the kidney while excreting potassium

            - under the influence of renin

 

            Too little aldosterone = hypoaldosteronism

                        - sodium and water are excreted

                        - potassium retained

 

                        ACE-inhibitors (“-prils”) for HTN do same thing

                                    (Watch for hyperkalemia in renal insufficiency patients.  Cut back on high-potassium foods:  potatoes, prunes, cantaloupe, salt substitute).

 

            Too much aldosterone = hyperaldosteronism

                        - too much sodium and water are retained (--> HTN)

                        - too much potassium is excreted (hypokalemia)

            Causes:  primary adrenal disorder (Conn’s disease = RARE), such as an aldosterone-secreting adenoma, or secondary cause such as from    excessive stimulation of the normal adrenal cortex by substances such as angiotensin, ACTH, or elevated potassium

 

OF MEDULLA:

 

            Catacholamines (Epi and NE)

 

            Too little:  no known physiologic alterations

 

            Too much:  caused by pheochromocytoma, a catecholamine-producing tumor ---> HTN

 

HORMONES OF THE PANCREATIC ISLETS OF LANGERHANS

 

Insulin

            Promotes utilization of glucose, lowers serum glucose

 

Glucagon

            Promotes utilization of glycogen, raises serum glucose

 

 

Diabetes Mellitus

Statistics

  • In the United States:
    • More than 20 million people currently have type 2 diabetes
    • Estimated that 50% may be undiagnosed
    • An estimated cost of more than $92 billion/year
  • Much of the cost of diabetes, both personal and economic, can be traced to inadequate glycemic control and treatment of comorbidities

 

Pathophysiology

  • 3 physiologic processes that normally regulate glucose levels are altered:
    • Production of glucose by the liver
    • Secretion of insulin by beta cells of the pancreas
    • Uptake of glucose in peripheral tissues stimulated by insulin activity
  • At early stage of disease, may develop resistance to insulin
  • Pancreatic cells compensate by increasing insulin release, resulting in hyperinsulinemia
  • This is associated with obesity and can exist undetected for many years (= “prediabetes” stage)
  • Insulin levels may then diminish
    • Does not allow for adequate compensation for insulin resistance
    • Hyperglycemia then occurs

 

Classifications

  • Type 1 Diabetes Mellitus (formerly known as Insulin-Dependent DM, or IDDM or Juvenile Diabetes)
    • Lack of effective insulin due to pancreatic beta cell depletion
    • Typical onset prior to age 40, Caucasian with northern European background, accounts for 5-10% of all diabetes
    • Associated with HLA DR-3, HLA DR-4, predisposition to autoimmune associated events with antibodies to insulin or islet cells; the antibodies appear three to four years prior to the overt onset of the disease
    • Unsure of what turns on the immune response

 

 

  • Type 2 Diabetes Mellitus (formerly known as Non-Insulin Dependent DM,  NIDDM, or Adult-Onset Diabetes)
    • Prevalence increases steadily with age with the usual onset after age 40
    • Accounts for 85-90% of all individuals with DM
    • Incidence in non-Caucasian groups compared to Caucasians:
      • African-Americans: 2:1
      • Mexican-Americans: 2.5-3:1
      • Native-Americans  5:1
      • In above groups, diet and lifestyle play a large role in the development of obesity and accompanying insulin resistance
    • Genes also play a role:  first degree relatives with Type 2 DM increases the risk; lifestyle increases risk (obesity, high calorie/high fat diet, sedentary lifestyle)…Not HLA!
    • Type 2 DM characterized by either:
      • Insulin resistance:  subnormal biological response to insulin due to either defect on target cells or defects in intracellular glucose transport
      • Insulin deficiency:  pancreatic islet cell dysfunction with glucose toxicity and islet cell dysfunction
    • Gestational diabetes:  impairment of insulin secretion and insulin action developing during pregnancy; associated with large babies (> 9-10 lbs.)
      • Maternal hyperglycemia crosses the placenta causing fetal hyperglycemia; the fetal pancreas increases the output of insulin—insulin is a growth factors and causes the baby to grow
    • Increased risk of progression to Type 2 DM
      • Women with history of gestational diabetes need to be screened frequently for development of Type 2 DM
  • Secondary diabetes due to carbohydrate intolerance
    • Exocrine pancreatic disease—cystic fibrosis
    • Cushing’s disease or syndrome—excess cortisol resulting in glycogenolysis
    • Drugs:  thiazide diuretics, prednisone, L-dopa, sympathomimetics (decrease epinephrine), propranolol (decreases insulin secretion)
  • “Prediabetes”—categories of “Impaired glucose tolerance” and “Impaired fasting glucose”--asymptomatic, without intervention high incidence of developing diabetes within 5-10 years; diet/exercise/weight loss needede

 

Review of Carbohydrate, Protein and Fat Metabolism

  • Immediately following a meal:  the post-prandial state (anabolic state) = high insulin, low glucagon
    • Insulin is an anabolic hormone.  It stores fat and sugar for you, stimulates protein synthesis and growth, and it prevents tissues from catabolizing or breaking down
  • The fasting state (catabolic state) = low insulin, high glucagon
    • Glucagon is a catabolic hormone.  It breaks down stored energy from glycogen and protein stores to produce glucose; the by-product of lipolysis is acetate which the liver oxidizes for energy.  Acetate is converted to ketoacids and ketone bodies.  With prolonged fasting the ketoacids increase as do free fatty acid levels, this in turn decreases the rate at which muscle protein is catabolized to amino acids and hepatic gluconeogenesis is subsequently decreased; the brain then uses ketoacids for energy.

 

Type 1 DM:  an absolute lack of insulin that, if untreated, results in an exaggerated fasting and catabolic state with weight loss.

  • With progressive failure of insulin secretion, the initial manifestation is postprandial hyperglycemia, due to endogenous glycogenolysis and gluconeogenesis; as the insulin deficiency becomes more severe, fasting hyperglycemia occurs.
  • When the serum glucose exceeds the renal threshold for reabsorption (approx. 180 mg/dL), glucose is spilled into the urine filtrate and is excreted as glycosuria
  • Glucose in the urine acts as an osmotic diuretic—resulting in polyuria, urinary electrolyte loss (Na, K, MG, Ph), dehydration and compensatory polydipsia (lose calories as well, leading to polyphagia)
  • Physiologic stress occurs, resulting in the hypersecretion of the hormones of stress and other so-called counter-regulatory hormones.  Cortisol, epinephrine, glucagons and growth hormone are all considered counter-regulatory hormones
    • Either impair insulin secretion or antagonize its action
    • In addition, cortisol, epinephrine and glucagon stimulate more glucose and continues the cycle of hyperglycemia and glucosuria
  • With progressive hyperglycemia the blood becomes hyperosmolar and through poorly defined mechanisms, polyphagia occurs,
  • Clinical manifestations
    • Polyuria, polydipsia, polyphagia, weight loss, lethargy, weakness, enuresis, vaginal yeast infections and/or bacterial skin infections (hyperglycemia changes the milieu of the vagina and also inhibits the ability of the segs/neutrophils to migrate into the tissues to fight bacterial invasion (also antibiotics don’t work as well if blood sugar > 180)
  • If the process is allowed to continue, or if the progression of the disease is rapid, accelerated lipolysis occurs; increases plasma lipids and free fatty acids; ketoacids are formed through oxidation via the liver; their rate of formation exceeds their peripheral utilization and renal excretion capacity; and accumulation causes metabolic acidosis with compensatory deep breathing (Kussmaul respirations) to blow off CO2 and H2O.  Ketones are excreted in the urine and act as an osmotic diuretic pulling more water and electrolytes out of the body.  Results in progressive dehydration, abdominal pain with vomiting, continuing acidosis, increasing serum glucose, and diminished cerebral oxygen utilized with impaired consciousness.

 

 

 

 

 

Type 2 DM—clinical manifestations

  • Metabolic derangements are not usually as severe.  With insulin resistance, serum glucose levels gradually increase; with increasing serum glucose levels the pancreas responds by increasing insulin output resulting in hyperinsulinemia
    • May be asymptomatic for 5-10 years. 
    • May have polyuria, polydipsia, polyphagia; weight gain due to increased insulin
  • Hyperinsulinemia acts as an “oxidant” and damages endothelial cells of the rteries, initiating the process of atherosclerosis
    • Important to reduce cholesterol and triglycerides
  • Hyperglycemia may damage the peripheral nerves and/or autonomic nerves
    • Peripheral neuropathy
    • Autonomic neuropathy (causes nocturnal diarrhea, impotence, tachycardia, postural hypotension, gastroparesis, impaired bladder emptyng)
    • Hyperglycemia > 180 mg/dl inhibits WBC’s – increased infections, especially skin, including foot ulcers that are unresponsive to therapy
    • Hyperglycemia affects the kidney, leading to presence of microalbuminuria
      • Use ACE inhibitors or ARBs to decrease angiotensin II, and dilate the efferent arteriole of the glomerulus; decreases intraglomerular blood pressure
    • Retinopathy—increased risk of blindness, partial loss of vision, cataracts, and glaucoma

 

Treatments

·         Diet: 50% of calories should be carbohydrates, 20% or less protein, 30% or less fat, plenty of fiber (unless gastroparesis)…slows glucose absorption and improves tolerance

  • Exercise improves glycemic control
  • Oral medications
  • Insulin
    • Use of insulin in the Type 2 DM patient:  uncontrolled hyperglycemia has a detrimental effect on the beta cells of the pancreas, resulting in decreased insulin production and secretion, which in turn results in an increase in serum glucose.  Early use of insulin may prevent further beta cell destruction by controlling hyperglycemia.
  • Incretin mimetics:  Byetta, Symlin

 

Insulin Resistance

  • Insulin resistance may contribute to development of CV risk factors (HTN, dyslipidemia, obesity, and atherosclerotic heart disease) years before onset of the hyperglycemia and diagnosis of DM

 

 

 

Metabolic Syndrome

  • Characterized by a group of metabolic risk factors in one person.  They include:
    • Central (abdominal) obesity
    • Atherogenic dyslipidemia (mainly high triglycerides and low HDL cholesterol — that foster plaque buildups in artery walls)
    • Elevated blood pressure (130/85 mmHg or higher)
    • Insulin resistance or glucose intolerance
    • Prothrombotic state (e.g., high fibrinogen or plasminogen activator inhibitor)
    • Proinflammatory state (e.g., elevated high-sensitivity C-reactive protein)
  • Underlying causes: overweight/obesity, physical inactivity and genetic factors.

How is the metabolic syndrome diagnosed?

·         The criteria proposed by the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) are the most current and widely used.

·         According to the ATP III criteria, the metabolic syndrome is identified by the presence of three or more of these components:

o   Central obesity as measured by waist circumference:
Men — Greater than 40 inches
Women — Greater than 35 inches

o   Fasting blood triglycerides greater than or equal to 150 mg/dL

o   Blood HDL cholesterol:
Men — Less than 40 mg/dL
Women — Less than 50 mg/dL

o   Blood pressure greater than or equal to 130/85 mmHg

o   Fasting glucose greater than or equal to 110 mg/dL

·         The ATP III panel did not find evidence to recommend routine measurement of insulin resistance (e.g., increased fasting blood insulin), prothrombotic state or proinflammatory state.

AHA Recommendation

·         To gain the most benefit from modifying multiple metabolic risk factors, the underlying insulin resistant state must become a target of therapy. The safest, most effective and preferred way to reduce insulin resistance in overweight and obese people is weight loss and increased physical activity.

·         Routinely monitor body weight (especially the index for central obesity), blood glucose, lipoproteins and blood pressure.

·         Treat individual risk factors (hyperlipidemia, hypertension and high blood glucose) according to established guidelines