Weatherly's Woes - Diabetes

DIABETES MELLITUS

Sweet pee

All of the pathophysiology and all of the symptoms of diabetes mellitus (DM) ultimately stem from a single problem -- too much glucose.

Glucose is sticky. If you spill some Gatorade, the surface will get sticky. The same stickiness happens on a molecular level. Glucose likes to spontaneously attach itself to any protein that it touches. This is called non-enzymatic glycosylation (NEG). If it happens enough, the protein can lose some function. Once a protein has become oversaturated with glucose, we call that an Advanced Glycosylated End-Product (AGE). These AGEs have a lot of crummy consequences, which are typically divided into (a) Macrovascular, (b) Microvascular, (c) Osmotic and (d) RBC.

Macrovascular damage refers to atherosclerosis. There is A LOT of it in diabetes. Atherosclerosis can affect the Aorta (AAA), Coronaries (MI, angina), Popliteal (claudication, foot ulcers) and Circle of Willis (SAH).

Microvascular damage refers to endothelial NEG. It makes the vascular BMs swell, which narrows the lumens. Perfusion falls, ischemia occurs. This affects the retina (patchy vision loss), kidney (hyperfiltration), neurons (vasa nervorum blockage) and arterioles (arteriolosclerosis causing HTN). CKD is very common. Peripheral stocking-glove neuropathy (sensory > autonomic > motor) is common too.

Osmotic damage occurs due to sorbitol. Sorbitol is an obscure sugar, it tends to be higher in diabetics. The problem is that humans have a “Sorbitol loophole” -- some organs lack the enzyme to degrade sorbitol (Aldose Reductase). So sorbitol accumulates. That draws in fluid, which disrupts the normal cellular architecture (note that sorbitol is also capable of oxidative damage). This can occur in the lens (cataracts) and peripheral nerves.

RBCs get coated by glucose via NEG. We can measure that stickiness. The HgA1C test measures the percentage of a certain amino acid that is glycosylated. In other words, it tells you how sugary their blood has been over the course of an RBC’s lifespan (about 3 months). This is the best diabetes test.

Other symptoms that aren’t due to NEG:
1. 1. 1. Insulin favors anabolism, or building stuff. Without insulin, catabolism reigns. Weight loss, muscle atrophy and fatigue ensue.
    2. Glucose is an osmotic diuretic. Hyperglycemia makes you pee a lot (polyuria). That will leave you thirsty (polydipsia) and dehydrated. Polydipsia and polyuria are the most common initial symptoms of diabetes.
    3. Bacteria love glucose. In hyperglycemia, the blood becomes a petri dish. That’s why diabetes causes immunosuppression.

Type 1 diabetes means no insulin

(autoimmune destruction of beta-cells in the endocrine pancreas)

Type 2 diabetes means not enough insulin receptors

(the tissues become resistant to insulin, high correlation with obesity)

TYPE 1 DIABETES MELLITUS

No insulin

Type 1 Diabetes Mellitus (DM1) means you can’t make insulin. Pancreatic beta cells make insulin (clustered into Islets of Langerhans). DM1 usually starts in teenagers. Polydipsia, polyuria, weight loss and fatigue are the first symptoms. If those aren’t noticed, it can progress into Diabetic Ketoacidosis (DKA). DKA is deadly, see DKA page for more information.

Type 1 diabetes is an autoimmune disease. T-cells kill the beta cells, a type 4 hypersensitivity. T-cells primed with HLA-DR3 or DR4 tend to hate beta cells. B-cells are recruited, and they make autoantibodies (antiglutamic acid decarboxylase, anti-islet cell autoantigen 512). Once 80% of beta cells are dead, you become symptomatic. The MOA is incomplete -- but involves a genetic predisposition (HLA) plus environmental triggers (viral infection).

Beta cells secrete insulin. They also secrete C-peptide, an inert structural byproduct of insulin synthesis. It can help you distinguish the cause of hyperglycemia. It’s low in DM1. It’s high in DM2. Some people abuse diabetic medications, and the C-peptide can help you here. It’s low with insulin. It’s high with sulfonylureas.

Type 1 Diabetes Treatment

Type 1 diabetes is treated with insulin, injected subcutaneously. Insulin is a clean drug -- the biggest side effect is hypoglycemia, which is kind of the whole point. But the therapeutic window is narrow -- diabetics must be cautious. Hypoglycemia triggers the sympathetic nervous system. That causes tachycardia, palpitations, tremors, sweating, etc. Hypoglycemia is called the “great imitator” because it can cause a lot of symptoms. That’s why glucose is the “5th vital sign.” The other side effect of insulin is weight gain (anabolism). There are different chemical formulations of insulin that dissolve into your blood at different speeds.

Rapid Acting Insulin (Lispro, Aspart, Glulisine) works almost immediately. Take it before meals. No LAG with Lispro, Aspart, Glulisine.

Regular Insulin (Humulin, Novolin) is made in a lab by genetically modified E. coli. It takes 30 minutes to kick in, peaks at 2 hours and wears off after 4 or 5 hours. Regular Insulin is the cheapest available type of insulin, because it’s been around a long time and because bacteria can pump out huge quantities. As the name implies, this is basically the same molecule as the insulin in our bodies. This makes it the “standard” form of insulin. Patients have to use a sliding scale to correlate their current blood glucose to adjust their dose. For some reason, this is the only Insulin that you can give IV, which makes it attractive for the treatment of serious conditions like DKA and HHS.

NPH Insulin - NPH stands for Neutral Protamine Hagedorn. Weird. This is just regular insulin that has been combined with a neutral protamine peptide. Protamine slows absorption. It lasts about 12 hours. It isn’t used much anymore, since better long-acting insulins have been introduced recently.

Detemir is long-lasting insulin. It’s given once or twice daily. Its insulin is attached to a fatty acid side chain that slows absorption.

Glargine is one of the longest lasting insulins. It provides a low, continuous level of insulin all day long. You can take it once daily! It has a modified amino acid structure that crystallizes at body pH, and then slowly dissolves.

Note - Insulin is measured in units. Units of what, you may be asking. One unit is defined as the amount of insulin required to lower the blood glucose by 50 (in the average patient).

TYPE 2 DIABETES MELLITUS

No insulin receptors

Type 2 diabetes mellitus is a state of pathological insulin resistance. It’s caused by obesity. It usually occurs in adults. There is plenty of insulin in the blood of diabetics. But the receptors get downregulated, so there’s nothing for insulin to bind to. It’s like having plenty of keys, without any keyholes. The beta cells are overworked in DM2. They eventually get tired, fill up with amyloid and die. From that point forward, the patient requires insulin treatment.

While DM1 starts pretty rapidly, DM2 can take years to progress to symptoms. That’s a problem! The early silent phase is reversible! Left untreated, permanent damage slowly occurs in the cardiovascular system, nerves, eyes and kidneys. So we screen for diabetes with the HgA1C test (>6.5%).

Secondary Causes of DM2

- - Gestational Diabetes is a temporary DM2 seen during pregnancy. The placenta wants to provide lots of nutrients for the fetus. So it makes Human Placental Lactogen. HPL purposely induces insulin resistance. That way mom becomes hyperglycemic, and the baby gets lots of sugar. In 2% of pregnancies, the placenta overshoots and causes diabetes.
  - Maturity-Onset Diabetes of the Young (MODY) is a genetic strain of DM2 that starts early in life, probably underrecognized. Fun fact - DM2 has a stronger genetic component than DM1.
  - Pancreatic Insufficiency, because if something damages the pancreas (Chronic Pancreatitis, CF, Iron), eventually it may affect the Islets.
  - Cushings raises Cortisol, which raises the glucose, which promotes Insulin Resistance. Same goes with GH.
  - Glucagon, weirdly enough, promotes Insulin secretion. A glucagonoma can promote diabetes.
  - Somatostatin inhibits insulin secretion, causing hyperglycemia. Somatostatinomas cause a particularly strong variant of DM2.

Type 2 Diabetes Drugs

First line treatment is a low carb diet and exercise. Exercise drains hyperglycemia by translocating GLUT4 without requiring insulin. In motivated patients, diet and exercise can be curative. But most will require medications, and eventually insulin.

Metformin is the first medicine you should choose. Its MOA is complex, but likely involves blocking gluconeogenesis. Metformin causes modest weight loss, which helps with patient adherence. It also doesn’t cause hypoglycemia. Since it doesn’t likely involve beta cells, Metformin can be used in advanced cases that have decimated their beta cells. The most common side effect is GI distress. But test makers will ask about Metformin’s risk of lactic acidosis in patients who also have renal insufficiency. This was seen in some case studies in the 1970s. In theory, metformin favors the conversion of glucose to lactate which can build up and precipitate lactic acidosis. In reality, there are many reasons to doubt the existence of Metformin lactic acidosis. But if asked, say that Metformin shouldn’t be given to those with CKD or CHF. It should also be held for a few days whenever IV contrast dye is given or the patient gets an AKI.

If Metformin alone isn’t working, then start stacking on any of the drugs below.

Sulfonylureas increase insulin secretion. The precise MOA is a little convoluted, but here goes. Sulfonylurea blocks K+ channels (in beta cells of course). This makes the cells more positive. When the cells reach a certain positive threshold (made easier thanks to Sulfonylurea), they generate an action-potential. Calcium floods into the cell. When the cell depolarizes, insulin is released. The problem with Sulfonylureas is that they can make you hypoglycemic. That’s because they tell the beta cells to make more insulin, no matter what! Insulin promotes weight gain, which is another predictable side effect of this class. But these drugs are cheap! First generations (Tolbutamide, Chlorpropamide) are not used in the modern era. Chlorpropamide inhibits Acetaldehyde DH, which causes a disulfiram-like reaction (flushing, tachycardia) when drinking alcohol. Chlorpropamide also increases ADH activity, and causes hyponatremia. Second generations (Glipizide, Glyburide) are the most commonly used formulations. Meglitinides (Nateglinide, Repaglinide) are non-sulfa versions used in sulfa allergies.

Thiazolidinediones (-glitazone, Pioglitazone) are pills that improve insulin resistance. They bind to PPAR-y receptors that are found in the nuclei of adipose tissue (side note, Fibrates activate PPAR-a). The TZD-PPAR duo then binds to retinoid X receptors, which modulates gene transcription.. Here are some theorized mechanisms: GLUT4 upregulation, Adiponectin release (increases insulin sensitivity) and TNF-a antagonism (TNF-a contributes to insulin resistance). The TZDs can cause weight gain (proliferation of adipocytes), hepatotoxicity and edema. So avoid TZDs in patients who already have edema (CHF).

The Glucosidase Inhibitors (Acarbose, Miglitol, Voglibose) are taken before meals, and they stop you from absorbing dietary sugar! They do so by competitive inhibition of intestinal a-glucosidases (e.g., enzymes like sucrase, maltase) found on the brush border of enterocytes. Predictably, these drugs mess with ya guts, causing GI upset (basically have constant lactose intolerance-like symptoms)!

You may not remember this, but Insulin is secreted with a sister molecule called Amylin. It’s not emphasized in medical education, because we honestly have no idea what it does. But it turns out that administering Amylin Analogs (Pramlintide) can improve coadministered insulin. Amylin has several mysterious effects, but just know that it suppresses glucagon release and allows insulin to work more effectively. It also reduces appetite! Like insulin, Pramlintide is injected SQ with meals. In fact, it has to be given alongside insulin. By potentiating Insulin, it can lead to hypoglycemia.

When you eat a delicious cheeseburger, your satisfied gut releases molecules called incretins. Incretins INCREase insulin release (kind of like endogenous sulfonylureas). Glucagon-Like Peptide 1 (GLP-1) and Glucose Insulinotropic Peptide (GIP) are examples of incretins. GLP-1 is released by L-cells, and GIP is released by K-cells (both of which reside in the small bowel). Incretins explain why eating a spoonful of sugar results in more insulin secretion than IV administration of that sugar. Type 2 Diabetics suffer from incretin insensitivity, so administering more incretins can help them regain their normal incretin-effect. One more thing. Incretin secretion is inhibited by something called DPP-4 (Dipeptidyl Peptidase 4).

GLP-1 Analogs (Exenatide, Liraglutide) are injected SC. Not much to say. They are potent weight loss drugs as well

DPP-4 Inhibitors (-gliptin, Sitagliptin, Linagliptin) block the molecule that blocks incretin release. Double negative I know, but the overall effect is increasing your incretins. These oral pills are taken once a day. They have a really weird side effect -- increased infections. DPP-4Is are less effective and have more side effects than GLP1s.

Wouldn’t it be nice if diabetics could just pee out their extra sugar? Thanks to evolution, our body is very reticent when it comes to freely losing glucose. The SGLT2 transporter found in the kidney is ruthlessly efficient when it comes to reabsorbing glucose in the proximal convoluted tubule. Thankfully, there are drugs that block this transporter. SGLT2 Inhibitors (-flozin, Canaglifolozin, Dapagliflozin) promote sugar diuresis (good drug of choice for concomitant CHF). They’re easy to remember since they end in -flozin and that should remind you of flowing urine. The side effects are also easy to remember if you keep in mind their sugary urine. The bladder becomes a very inviting target for hungry bacteria, and these patients are more likely to get UTIs. They also get more vaginal candidiasis for some reason. They can lead to mild weight loss, yay! And since these drugs work on the kidneys, you probably shouldn’t use them on someone with CKD. Some recent evidence suggests that SGLT2 inhibitors have some incredible cardiovascular benefits. In a few years, I wouldn’t be surprised if most adult patients will be taking one.

DKA & HHS

Acute diabetes

Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar Syndrome are the acute lethal manifestation of poorly managed diabetes. They cause life-threatening dehydration. They are pretty similar, so it’s a little easy to confuse them. DKA is more common in DM1. HHS is more common in DM2.

This may be obvious, but the name “DKA” helps me remember the lab findings

Diabetic - Hyperglycemia

Keto - Ketones in the urine

Acidosis - low pH

Note that the diagnosis and treatment of DKA is more complicated than I’ve made it out to be. Begin by giving lots of fluids and administering regular insulin. Then check the potassium. It must be closely monitored during treatment. Insulin drives potassium into cells, and so it can swing rapidly during treatment. Also keep in mind that serum potassium does not equal total body potassium (which cannot be measured). One other weird caveat is that it's possible to have "euglycemic DKA" but it's a higher level concept.