Carnegie 6

Physiology of Glucagon

• hormone of the postabsorptive state

• 29-amino acid polypeptide: a very potent hyperglycemic agent

• **secretion of glucagon is stimulated by a drop in blood glucose concentration **

• interestingly, secretion also stimulated by a rise in blood amino acid concentration

Hyperglycemic agent

Able to raise blood sugar levels

Fasting state

blood glucose 3.33-5.56 mmol/L; rises to 6.67-7.78 mmol/L after a meal; should return to normal range ~2 h later and we need that level to be maintained

Why is it important to maintain blood glucose levels???

glucose is your body's main energy source, especially for the brain, and fluctuations affect mood, focus, and energy, while long-term imbalance leads to severe issues like heart disease, nerve damage, and diabetes complications

At least 50% of all glucose formed by gluconeogenesis during the postabsorptive state is used by what?

the brain

Glycogenolysis in liver

liver has ~100 g of glycogen reserves; enough to maintain blood glucose ~4-6 h during postabsorptive state

Glycogenolysis in skeletal muscle

another 100 g (4-6 h) of glycogen reserves; 2-step process, involving liver in second step, to release glucose to blood

Lipolysis in adipose tissue, liver

products are glycerol (to liver for gluconeogenesis) and fatty acids (chopped into 2-carbon fragments to produce acetyl CoA - cannot be converted to glucose but do provide an alternate energy source via Krebs cycle)

Catabolism of protein to produce amino acids for gluconeogenesis

used if fasting is prolonged & other options becoming exhausted

Glucose sparing

most tissues are stimulated to use noncarbohydrates (lipids) to spare glucose for brain; instead, they will use fatty acids & ketone bodies for ATP production

Making glucose available to the blood

• Glycogenolysis in liver

• Glycogenolysis in skeletal muscle

• Lipolysis in adipose tissue, liver

• Catabolism of protein to produce amino acids for gluconeogenesis

Glycerol

can go back up through glycolysis to produce glucose, but 2 carbon pieces (acetyl groups) of fatty acids can only add to CoA and insert into Krebs cycle as acetyl CoA and provide energy

Ketone bodies

acetyl CoA not entering the Krebs cycle is converted (liver) to acetoacetate, b-hydroxybutyrate, and acetone (may be reconverted to acetyl CoA or accumulate in blood)

Back-up Hormones/Systems for Glucagon

• Sympathetic Nervous System

• Cortisol

• Growth Hormone

• Thyroid hormone

Back-up Hormones/Systems for Glucagon- Sympathetic Nervous System

• in response to injury, anxiety, anger, . . Þ sudden drop in blood glucose

• adipose tissue is well-supplied with sympathetic nerve fibers

• adrenal medulla also releases E in response to sympathetic stimulation

  • mobilizes fats

  • stimulates glycogenolysis

  • stimulates gluconeogenesis

Back-up Hormones/Systems for Glucagon- cortisol

• secretion increased by long-term stressors, eg. hemorrhage, surgery,

• infections, physical or emotional trauma, vigorous exercise, . . .

  • mobilizes fats

  • stimulates gluconeogenesis

  • stimulates protein catabolism

In cushing’s syndrome, a symptom is persistent hyperglycemia that can put a person at risk of developing type 2 diabetes – how?

Too much cortisol stimulates insulin release, over longterm, beta cells tend to get overstimulated and become less affective

In Addison’s disease, hypoglycemia is a symptom (hormone replacement therapy for both cortisol and aldosterone is required)- why?

Any sort of stress, no cortisol to stimulate processes, needs hormone replacement therapy

Back-up Hormones/Systems for Glucagon- Growth hormone

• primarily an anabolic hormone, but also:

  • mobilizes fats

  • reduces glucose uptake by muscles

  • stimulates protein synthesis and inhibits protein degradation

Back-up Hormones/Systems for Glucagon- Thyroid hormone

• primary role is to increase BMR

• mixture of insulin-like and glucagon-like actions

  • stimulates glucose oxidation to provide energy

  • mobilizes fats

  • stimulates uptake of amino acids to promote protein synthesis

2 minor players in the day-to-day regulation of metabolism

GH and Thyroid hormone

They have other very important primary actions, but they can also influence some aspects of metabolism as a result of those primary actions.

Explain why diabetes mellitus is described as “Famine in the Midst of Plenty”

• A metabolic disorder due to lack/absence of insulin, insulin resistance, or both. As a consequence, glucose cannot be used properly, leading to altered metabolism of fats & proteins. (cant make insulin, lots of glucose in blood that cant be taken in by cells and used)

• “The chronic hyperglycemia of DM is associated with significant long-term sequelae, particularly damage, dysfunction and failure of various organs - especially the kidney, eye, nerves, heart and blood vessels.”

Two main types of diabetes mellitus

(1) type 1: insulin-dependent diabetes mellitus (IDDM)

(2) type 2: non-insulin-dependent diabetes mellitus (NIDDM)

Type 1 Diabetes Mellitus (10% of cases)

• primarily a result of b-cell destruction; prone to ketoacidosis

• plasma insulin low; responds poorly or not at all to rise in glucose

• b-cell destruction; islet cell antibodies (ICAs)

• viruses often suspected trigger; onset often after infections (mumps, rubella, measles, . .) - autoimmune response extends to b-cells

• absolute deficiency of insulin Þ hyperglycemia, enhanced lipolysis & protein catabolism; individuals prone to ketoacidosis; require insulin

Type II Diabetes Mellitus (90% of cases)

• adult-onset, usually after age 30; 70-80% of patients are obese (adiponectin and insulin sensitivity)

• ~80% of cases correlated with a positive family history

• insulin production at birth but also a level of insulin resistance

• insulin resistance initially overcome by increased insulin secretion; finally, b-cells begin to become exhausted

• not prone to ketoacidosis; usually do not require insulin – but may require other medications to reduce gluconeogenesis, address insulin resistance

Describe the laboratory tests used to diagnose diabetes mellitus

• Fasting Plasma Glucose (FPG)

• Oral Glucose Tolerance Test (OGTT)

• Glycosylated Hemoglobin

Fasting Plasma Glucose (FPG)

• up to 1998, cut-off was 7.8 mmol/L (signaled ~40% of diabetic cases)

• measure early AM, at least 8 h after last meal

• cut-off level of 6.67 mmol/L (120 mg/dL) is more sensitive and agrees more closely with OGTT results (second step for all patients > 6.67 mol/L)

Oral Glucose Tolerance Test (OGTT)

• Underlying principle: a nondiabetic can absorb a given amount of glucose from blood faster than a diabetic

• Oral glucose load:

  • 75 g/ 2 h test

  • 100 g/ 3 h test

• levels should peak, then return to normal within 2-3 h; urine should remain free of glucose

Glycosylated Hemoglobin

• glycosylated Hb = hemoglobin A1c (Hb1c)

• formed slowly & irreversibly during the120-day lifespan of RBC

• levels usually <5% of Hb – that is normal

• amount of Hb1c increases in response to elevated [blood sugar]

• good diabetic control should maintain level < 6%

• test provides information on control of blood glucose over an interval of time, rather than blood glucose levels measured on a particular day

• will differentiate between poor control during preceding few months and an acute illness which has elevated blood glucose

Basic Clinical Signs of Diabetes Mellitus

• Polyuria

• Polydipsia

• Polyphagia

Polyuria

excess glucose in filtrate prevents water reabsorption by kidneys; excess urine production also associated with loss of Na+ and K+ as body strives to get rid of excess, negatively charged ketone bodies

Polydipsia

dehydration (water loss in urine) stimulates hypothalamic thirst centres

Polyphagia

excessive hunger & food consumption because person is actually starving - unable to use ingested carbohydrates

DM also characterized by what?

weight loss & weakness; at risk for infections (hyperglycemia interferes with neutrophil function)

Acute Complications of Diabetes Mellitus

• Diabetic Ketoacidosis

  • type 1 diabetes

• Hyperglycemic, hyperosmolar, nonketotic (HHNK) Coma

  • type 2 diabetes

  • sufficient insulin that ketone body accumulation is not a concern

  • extreme dehydration due to excessive gluconeogenesis

  • often seen in elderly type 2 diabetics who may be going through a stress of longer duration (recovery from surgery, bad bout of the flu, . . . )

• Insulin Reaction

  • hypoglycemia occurs often as a consequence of insulin therapy, etc.

    • insulin overdose

    • inadequate food intake

    • increased amount of exercise

    • nutritional/fluid imbalances due to nausea/vomiting

• The key issue is glucose deprivation to the brain