L31: Biochemistry of DM

Question 1

Prevalence of DM

Answer 1

• 8.3 % of total population have diabetes - Prevalence is age-dependent: 3.7% on 20-44 grp, 13.7% in 45-64 grp and 26.9 % in >= 26.9%

Question 2

Etiology of type I diabetes, type 2 diabetes and gestational diabetes

Answer 2

• Type 1: autoimmune destruction of insulin producing cells - Type 2: acquired insulin resistance - Gestational diabetes: far down-regulation of insulin sensitivity of mother during pregnancy

Question 3

Complications of diabetes (most devastating):

Answer 3

• Retinopathy - Nephropathy - Neuropathy

Question 4

Tissue level impact of diabetes:

Answer 4

• Energy stores not refilled after meal, tissues chronically starved - High concentration of glucose in circulation damages blood vessels - High osmotic pressure leads to dehydration of tissues

Question 5

Impact of diabetes on glucose and FA metabolism.

Answer 5

1.) Glucose: Insulin has no impact on liver, fat and muscles, as a result: - Glucose comes in, remains in serum - Liver receives AA from muscles and performs gluconeogenesis - Fat leaves adipose and enters liver, where ketone bodies are generated 2.) Lipids: insulin does not activate LPL and deactivate HSL, as a result: - Chylomicrons carrying dietary TAG stay in serum and cannot enter adipose via action of LPL - HSL is on and is performing lipolysis, TAGS are degraded into FAs, which enter circulation and travel to liver. FAs are generated in excess of what is needed to generate ketone bodies. As a result, TAGs are synthesized and packaged into VLDL, which become elevated in blood.

Question 6

Match the following to presentation of diabetic patients: hyperglycemia, hyperlipidemia, ketoacidosis, occasional hypoglycemia. Treatment?

Answer 6

• Type 1: hyperglycemia, hyperlipidemia, ketoacidosis and occasional hypoglycemia. Treatment = exogenous insulin. - Type 2: hyperglycemia, hyperlipidemia. Also NKHS, HHS and NKHHC. Treatment = insulin, but when ineffective, must use other methods: drugs to stimulate insulin, sensitizing tissues to insulin, reducing intestinal absorption of glucose, repressing gluconeogenesis etc.

Question 7

Which diabetic pt presents with occasional hypoglycemia? Why? What is treatment?

Answer 7

• Type 1: too much insulin taken. Treatment = glucose and glucagon

Question 8

Why do T1 diabetic pts often present with DKA whereas type 2 don’t?

Answer 8

• Function of insulin in addition to glucose metabolism is to repress ketone body production and inhibit lipolysis. - In absence as is case with T1 diabetics, large amounts of FFAs are released, ketogenesis ensues and ketoacidosis results. - Lipolysis is seen in T2 diabetics, but not as much as insulin is still available in large amounts and does have somewhat of an effect of repressing lipolysis.

Question 9

Explain the role of sorbitol in the pathology of diabetes

Answer 9

• In DM pts, there is more free glucose in the cells than in other pts. This is a result of many things, including the failure of phosphorylation by hexokinase/glucokinase. This turns on aldose reductase, which uses NADPH to general sorbitol, which is used by polyol DH to form fructose, consuming NAD. As a result, antioxidant defenses that rely on NADPH are weakened and NADH is high, so glycolytic capacity is reduced. - Sorbitol also is osmotically active and draws water into cells, distorting cellular/tissue structure

Question 10

Impact of high blood sugar on nerves, blood and renal vessels.

Answer 10

• General angiopathy: high sugar levels damage walls of both small (microangiopathy) and large (macroangiopathy). Damage to large vessels leads to stroke and MI. Damage to small vessels leads to necrosis to highly vascularized and oxygen-dependent tissues (retina = blindness, glomeruli = kidney nephrons = kidney failure) - Neuropathy: loss of function of peripheral nerves – numbness and tingling in extremities.

Question 11

Describe synthesis of insulin

Answer 11

• Insulin polypeptide synthesized on ribosomes – enters ER as preproinsulin - Cleaved and folded into proinsulin - Leaves ER and travels to Golgi where it is cleaved to c-peptide, A and B chain, which are all excreted out of the cell. Functional insulin = A and B chain bonded together

Question 12

Molecular action of insulin

Answer 12

• Binds to IR in PM of target cells - IR = kinase, phosphorylates itself then IRS - Phosphorylation cascade ensues, but at level of enzymes, dephosphorylation occurs via phosphatase - Cell undergoes dramatic changes in protein activation, protein localization and gene transcription

Question 13

Describe changes in mRNA levels that occur as a result of insulin binding

Answer 13

• Increase in acetyl-CoA carboxylase and FA synthase - Decrease in PEP carboxykinase