Setting: office
CC: “I am here to follow up on my medication.”
VS: blood pressure: 134/94 mm Hg; pulse rate: 84 beats/minute
HPI: A 54-year-old man, who was diagnosed with diabetes last year, comes to your office for a follow-up appointment. He was placed on metformin and a sulfonylurea, which controlled his glucose levels for most of the last year. Currently, he has started to have some episodes of nocturia one to two times a night. He insists he is fully adherent to his medications.
PMHX:
Hypertension
Hyperlipidemia
Microalbuminuria
Medications:
Metformin, atorvastatin, lisinopril, glimepiride
Initial Orders:
HbA1c
CHEM-7
LFTs
UA, urine microalbumin
Lipid panel (LDL, HDL, triglycerides, total cholesterol)
The patient returns 1 week later to receive the results of his laboratory tests:
HbA1c: 7.8%
Serum glucose: 195 mg/dL
UA negative for protein, small glucose found; positive urine microalbumin
Transaminases normal
LDL: 80 mg/dL, others normal
Microalbuminuria is caused by a loss of negative charges on the glomerular basement membrane.
Statins cause LFT elevation much more often than causing creatinine kinase level elevation.
The HbA1c goal level is <7%.
Although the patient’s HbA1c concentration is not much above the target, he is having a recurrence of his symptoms of polyuria. Also, the goal of BP in a diabetic is <130/80 mm Hg. You have to add an additional agent. It is not clear which medication to add as the second drug in a diabetic.
Where is the majority of glucose absorbed in the nephron?
a. Proximal tubule
b. Loop of Henle
c. Distal tubule
d. Collecting duct
Answer a. Proximal tubule
One hundred percent of glucose should be absorbed by the end of the proximal tubule. There should be no glucose entering the loop of Henle. Some nephrons begin to saturate the SGLT transporter at a serum glucose level of 200 mg/dL. This is “threshold.” All are saturated at glucose level 375 mg/dL. Any rise in serum glucose level above 375 mg/dL will go straight into the urine.
Insulin has no effect on the secondary active transport of the proximal tubule.
Any Glucose in Urine = Some Blood Glucose Levels >200 mg/dL
The transport maximum for the tubule 375 mg/dL.
No further increase in reabsorption is possible.
You add a calcium channel blocker or beta-blocker as the second antihypertensive agent. Never combine an ACE inhibitor and an angiotensin receptor blocker (ARB). Even though the mechanisms are different, there is no efficacy in combining them. Besides BP control, there is nothing more you can do to prevent proteinuria when a patient is on an ACE inhibitor.
Orders:
Amlodipine
Sitagliptin
Continue lisinopril, atorvastatin, metformin, glimepiride
Thiazolidinediones (rosiglitazone)
• Increase peripheral insulin sensitivity
• Contraindicated in congestive heart failure (CHF) and fluid overload
Glucose reabsorption is by secondary active transport with sodium.
It is the same mechanism in the small bowel.
DPP-IV breaks down incretins (GIP and GLP).
The patient does not return for 2 months. He says, “I am fine; my fingersticks are all 110 to 135 and my home BP monitor shows 110 over 70 to 125 over 75.” His nocturia has resolved. His weight is 7 lb less than the last visit, which you ascribe to the DPP-IV inhibitor, sitagliptin. He is sometimes constipated by it, but it does not bother him.
What is the mechanism of weight loss with DPP-IV inhibitors?
a. GIP slows gastric motility.
b. Lower glucose slows motility—glucose is cathartic.
c. GLP stimulates motilin release.
d. DPP-IV drugs decrease acetylcholine.
Answer a. GIP slows gastric motility.
Gastric motility is directly slowed by incretins such as GIP. The old name for GIP was “gastric inhibitory peptide.” Motilin does increase gastric motility, but GLP does not stimulate it. The other gastrointestinal (GI) tract hormones secretin and cholecystokinin also decrease gastric motility. DPP-IV inhibitors block the metabolism of incretins. Exenatide and liraglutide on injectable medications that are long-lasting synthetic incretins.
Exenatide (synthetic GIP produces significant weight loss by slowing stomach motility.
Calcium channel blockers also cause constipation by inhibiting intestinal smooth muscle.
The patient’s current vital signs and laboratory test results are:
BP <130/80 mm Hg
LDL <100 mg/dL
HbA1c <7%
On CCS, if you are moving the clock forward and if the case does not end, it may mean it is waiting for you to do routine health maintenance and preventive medicine.
Orders:
Dilated ophthalmologic examination (refer to ophthalmology)
Monofilament examination of the feet
The eye examination shows nonproliferative retinopathy at this time. The foot examination is normal. The patient is maintained for a long time on the same medications. If your case shows complicationson a return visit much later, the responses are:
Neuropathy: Start gabapentin, lamotrigine, or pregabalin.
Constipation or diabetic gastroparesis: Start erythromycin or metoclopramide.
Proliferative retinopathy: Inject vascular endothelial growth factor (VEGF) inhibitors or do laser photocoagulation.
Mechanism of Complication of Diabetes
Neuropathy:
• Peripheral nerves have blood vessels feeding them or “vasonervorum.” Diabetes damages this microvasculature and starves peripheral nerves.
Gastroparesis:
• Diabetics have a decreased ability to sense gastric and intestinal distention, which is a part of neuropathy that also affects GI tracts.
• Motilin is decreased; erythromycin increases motilin release.
Proliferative Retinopathy:
• Blood flow to the retina is decreased from microvascular insufficiency.
• Distal vessels release humoral factors that stimulate vessel growth.
• Overgrown vessels in the retina block vision (Figure 3-2).
• VEGF inhibitors stop the abnormal new vessels from growing and blocking vision.
• Ranibizumab and bevacizumab are VEGF inhibitors that stop macular degeneration and inhibit diabetic retinopathy.
• Laser photocoagulation decreases production of these growth factors (Figure 3-3).
Figure 3-2. Diabetic retinopathy. Neovascularization of the disc. (Reproduced with permission from LeBlond RF, et al. DeGowin’s Diagnostic Examination, 9th ed. New York: McGraw-Hill; 2009.)
Figure 3-3. Panretinal photocoagulation is the application of laser burns to the peripheral retina. The ischemic peripheral retina is treated with thousands of laser spots to presumably eliminate vasogenic factors responsible for the development of neovascular vessels. Laser spots cause scarring of the retina and choroid, and scars may be hypotrophic (white spots) or hypertrophic (black spots). (Reproduced with permission from Paul D. Comeau.)