Setting: office
CC: “I get thirsty a lot.”
VS: R: 12 breaths/minute; BP: 144/92 mm Hg
HPI: A 53-year-old man comes for evaluation of his borderline high blood pressure (BP) and some intermittent sense of increased thirst. The patient has had BP readings of 134/86 mm Hg, 148/96 mm Hg, and 142/90 mm Hg on the last three visits. He has been reluctant to start antihypertensive medications and, instead, has been trying to correct it with exercise and weight loss. He has been trying for 9 months. His weight has increased by 4 lb.
PMHX: obesity
ROS: increased frequency of urination, no burning, no urgency, no hesitancy
Medications: none
PE:
General: comfortable
Heart, Lung, Abdomen: normal
Initial Orders: (obtained fasting)
Basic metabolic panel (CHEM-7)
Complete blood count (CBC)
Urinalysis (UA)
Glycated hemoglobin (HbA1c)
Lipid panel (low-density lipoprotein [LDL], high-density lipoprotein [HDL], triglycerides, total cholesterol)
If the case gives the option for examining laboratory test results on the same day as the original visit, do so. If not, then reschedule the patient for the following week on the computer-based case simulation (CCS).
Always do an “Interval History” on any patient returning for a new office appointment.
There is no change in the patient’s symptoms of intermittent thirst and inability to control his weight with diet and exercise.
Laboratory Test Results:
CHEM-7: glucose 218 mg/dL; blood urea nitrogen (BUN) 22 g/dL; creatinine 0.7 mg/dL; bicarbonate 24 mEq/L; potassium (K) 4.0 mEq/L
CBC: normal
UA: mild glucose (100 mg/dL); no white blood cells, no red blood cells
HbA1c: 8.4%
Lipid panel (LDL, HDL, triglycerides, total cholesterol): LDL 145 mg/dL, others normal
Obesity increases annually and so does diabetes.
Adipose tissue must have insulin for glucose to enter.
More Obesity = More Tissue Resistance = More Insulin Need
Insulin uses a tyrosine kinase receptor (Figure 3-1).
Figure 3-1. Model of insulin receptor signaling. The insulin receptor is composed of two and two subunits linked by disulfide bonds. Binding of insulin to the extracellular subunits activates a tyrosine kinase present in the cytoplasmic domain of the subunit. The activated kinase autophosphorylates specific tyrosine residues in the subunit. Receptor kinase activation is also the critical first step in a cascade of intracellular events that begins with phosphorylation of multiple docking proteins (insulin receptor substrates [IRSs]). Once activated, these multifunctional proteins initiate complex intracellular signaling pathways. Binding of IRS to phosphatidylinositol 3′-kinase (PI3-K) initiates one of the major pathways effecting carbohydrate, protein, and lipid metabolism, including translocation of the glucose transporter, GLUT-4, to the cell surface and the inactivation, by phosphorylation, of glycogen synthase kinase 3 (GSK3) and subsequent dephosphorylation and activation of glycogen synthase, thus stimulating glucose storage. In contrast, mitogenic effects of insulin are mediated by a mitogen-activating protein (MAP) kinase pathway. (Reproduced with permission from McPhee SJ, Hammer GD. Pathophysiology of Disease: An Introduction to Clinical Medicine, 6th ed. New York: McGraw-Hill; 2010.)
Lifestyle modifications of weight loss and exercise have already failed in this patient. You should stil l order “Advise,” “Educate,” and “Counsel” for both as well as a diabetic diet. However, given the increase in weight despite 6 months of previous efforts, you need to start medications. The same is true for hyperlipidemia. Metformin is the best initial therapy for obesity-related type 2 diabetes. It will not cause hypoglycemia and it will not increase weight. Sulfonylurea medications will do both of these things.
If people could do it, weight loss and exercise would eliminate 25% of diabetes immediately.
Exercising muscle does not need insulin.
Resting muscle does need insulin.
What receptor is affected most by exercise?
a. GLUT1 in brain
b. GLUT2 in kidney and bowl
c. GLUT3 in neurons
d. GLUT4 in skeletal muscle
Answer d. GLUT4 in skeletal muscle
Exercise does not affect any of the glucose transporters except the one in skeletal muscle.
Diagnosis of Diabetes
• HbA1c >6.5%
• Two fasting glucose test results >125 mg/dL
• Oral glucose tolerance test
• Single glucose test result >200 mg/dL with symptoms
Orders:
Metformin
Statin medication
Advise weight loss, exercise, diabetic diet
Salt-restricted diet
Nutrition evaluation
Urine microalbumin
Neural tissue does not use insulin for glucose transport.
What is the mechanism of the patient’s polyuria?
a. Saturation of SGLT2 in the proximal tubule
b. Insufficient insulin at the kidney tubule
c. Deficient antidiuretic hormone (ADH) effect at the collecting duct
d. Deficient ADH release from the posterior pituitary
e. Saturation of glucose transporters in the distal tubule
Answer a. Saturation of SGLT2 in the proximal tubule
The threshold for beginning to spill glucose into urine is a serum glucose level above about 180 to 200 mg/dL. This level drops with age and older people will spill glucose into urine at a lower blood level. The receptor for glucose on the tubule lumen side is the SGLT2. This is a cotransporter with sodium. Transport maximum for the tubule is about 375 mg/dL. This means all glucose reabsorption is fully maximized at all the tubules at a serum glucose level of 375 mg/dL. Between 200 and 375 mg/dL, you can still increase glucose reabsorption because not all the nephrons hit 100% saturation at the same blood level.
Nephrons are a “parallel circuit.” Not all saturate at the same glucose level.
SGLT2 receptors in the kidney are in the proximal tubule.
The patient returns in 1 week. His symptoms of thirst and polyuria have already improved. He had been getting up three times a night to urinate and now it is only once. He is fully adherent to metformin and statin. His BP is 138/92 mm Hg, and microalbumin is present in his urine.
Metformin works by blocking gluconeogenesis.
Drugs that increase insulin level drive glucose and lipids into cells, including adipose tissue cells.
Because metformin does not increase insulin level, it does not increase weight gain.
Because the patient has microalbuminuria, an angiotensin-converting enzyme (ACE) inhibitor should be started. All ACE inhibitors are totally identical therapeutically in terms of their benefit. The only difference is dosing, which is not covered on CCS. The BP goal in a diabetic patient is <130/80 mm Hg, so this patient needs to start an ACE inhibitor to control BP as well. There is no point in checking the HbA1c level so soon after starting oral hypoglycemic medications. It takes 1 to 2 months for HbA1c to have a meaningful change.
Red blood cells live 90 to 120 days. HbA1c measures average glucose over this time.
Orders:
ACE inhibitor (enalapril, lisinopril, ramipril)
Serum glucose
What is the mechanism of ACE inhibitor benefit for microalbuminuria?
a. Dilation of afferent arteriole increases glomerular filtration rate (GFR).
b. Dilation of efferent arteriole decreases glomerular hypertension.
c. Decreased BP protects the tubules.
d. Aldosterone inhibition affects the kidney.
Answer b. Dilation of efferent arteriole decreases glomerular hypertension.
Angiotensin II (ANGII) normally constricts the efferent arteriole. ACE inhibitors inhibit ANGII and dilate the efferent arteriole. This will have a brief effect on decreasing GFR, but overall, decreasing intraglomerular pressure protects the kidney vasculature from damage. This is similar to how decreasing hypertension decreases the risk of stroke or coronary disease. Briefly, there is decreased perfusion pressure, but in the long term, it protects the vasculature of both the brain and the heart.
ACE inhibitors decrease hydrostatic pressure in the glomerular capillary.
Metformin is contraindicated in renal insufficiency to avoid lactic acidosis.
The patient is given prescriptions for lisinopril, metformin, and a statin. A prescription is also given for a home BP monitor and fingerstick glucose monitoring. He returns in 2 weeks and his BP is 132/84 mm Hg. His home glucose test results are: 182 mg/dL, 170 mg/dL, 184 mg/dL, 165 mg/dL.
Because the patient’s glucose levels are not fully controlled on metformin, add a second agent. It is not clear which one to use and the Step 3 examination will not ask you unless there is a specific contraindication to one of them.
Everyone on a statin should have aspartate aminotransferase (AST) and alanine aminotransferase (ALT) checked.
Orders:
Add a second oral hypoglycemic medication.
Sulfonylurea (e.g., glyburide, glipizide, glimepiride)
Thiazolidinedione (e.g., rosiglitazone)
Dipeptidyl peptidase IV (DPP-IV) inhibitor (e.g., sitagliptin, saxagliptin, linagliptin)
Order liver function tests (LFTs)
Bring the patient back in 1 week to the office. The second agent will have started to work, but sulfonylureas may not have a peak effect for 2 to 3 weeks. If your case presents a person 2 to 3 months after the start of treatment, obtain an HbA1c measurement.
Mechanism of Action
• Sulfonylurea increases insulin release from the pancreas.
• Thiazolidine increases peripheral insulin sensitivity.
• DPP-IV blocks the metabolism of incretins and increases the level of glucagonlike peptide (GLP) and glucose-dependent insulinotropic peptide (GIP).
Incretins (GIP and GLP) increase insulin and decrease glucagon release from the pancreas.
The patient returns in 2 weeks and he is on two oral hypoglycemic medications. His BP is 124/78 mm Hg. His home glucose test results are: 124 mg/dL, 136 mg/dL, 120 mg/dL, and 128 mg/dL. The goal of LDL is <100 mg/dL in diabetes because it is an equivalent of coronary disease. Keep moving the clock forward doing vaccinations and health maintenancein diabetes until you get the screen that says, “Case ends in 5 minutes of real time.” The complication of diabetes and routine preventive medicine will be covered in the next case.