Diabetes Mellitus

After diagnosis, surviving β-cells can rally briefly and insulin needs drop, sometimes to as low as 0.1-0.4 units/kg/dayinstead of the usual 0.5-0.6. Don't mistake this for a cure. It's a temporary reprieve before ongoing autoimmune destruction finishes the job and full-dose lifelong insulin becomes non-negotiable again.

GAD65, ZnT8, and IA-2 are the islet autoantibodies used to confirm the autoimmune process and to stage presymptomatic disease (stage 1-2, see classification above). You don't need to memorize what each one binds, just recognize them as "T1DM autoantibody" on a vignette.

Cuts hepatic glucose output and improves peripheral (muscle) insulin sensitivity. Drops A1C by roughly 1.5-2%and FPG by 60-80 mg/dL in drug-naive patients. It's first-line because of the whole package: strong efficacy, essentially zero hypoglycemia risk alone, weight neutral to slightly weight-losing, decades of safety data, cheap, and a plausible CV benefit.

GI upset (diarrhea, cramping, nausea) is the main tolerability issue, minimize it by starting at 500 mg, going up in 500 mg increments over weeks, dosing with food, and using the XR formulation if needed (though XR doesn't clearly beat IR for GI tolerability in trials). Watch for B12 deficiency with long-term use, check levels annually or when suspected.

Hold before IV contraststarting the day of the procedure, resume 2-3 days later once renal function is confirmed stable, this protects against the acute kidney injury/lactic acidosis combination.

Block glucose reabsorption in the proximal tubule so excess glucose just leaves in the urine. Works independent of insulin, which is why it doesn't cause hypoglycemia alone and still works late in disease when β-cells are largely gone.

Glucose-lowering effect fades below eGFR 45, but the CV, HF, and CKD protective benefits persist even as glycemic benefit fades, and current guidance says it's fine to start as low as eGFR 20 and continue through dialysis if tolerated.

Stimulate glucose-dependent insulin release, suppress inappropriate glucagon, slow gastric emptying, and boost satiety centrally. Short-acting agents (exenatide, lixisenatide) mostly blunt postprandial spikes; long-acting agents (dulaglutide, liraglutide, weekly semaglutide, tirzepatide) hit both fasting and postprandial glucose and have the strongest weight-loss and A1C effects in the non-insulin lineup.

GI side effects (nausea, vomiting, abdominal pain) are dose-related and usually transient, titrate slowly and there's rarely a reason to rush. Counsel patients to eat slowly, stop at the first sign of fullness, and favor smaller, lower-fat meals early in treatment.

Watch for counterfeit products given the current market demand, and remind patients that unused pens need refrigeration while in-use pens are stable at room temperature.

Sulfonylureas(glimepiride, glipizide, glyburide) squeeze insulin out of the pancreas by binding SUR1. Strong A1C lowering (1.5-2%), cheap, oral, but carry the class's defining risk: hypoglycemia, plus weight gain and a tendency to lose effectiveness over time as β-cells keep failing regardless of the drug. Avoid glyburide in older adults and CKD, its active metabolites accumulate and stack the hypoglycemia risk.

Meglitinides(repaglinide, nateglinide) work at a site next to the sulfonylurea receptor but with a much faster onset/offset, taken with each meal. Useful for erratic eating schedules or renal impairment where sulfonylureas are riskier, but three-times-daily dosing hurts adherence and their evidence base is thin, they're not in the standard ADA algorithm.

TZDs(pioglitazone) improve peripheral and hepatic insulin sensitivity via PPAR-γ. High efficacy and durable, but cause dose-related fluid retention, weight gain, and increased HF risk, so they're contraindicated in NYHA III-IV HF and used cautiously in I-II. Also watch for bone fracture risk in postmenopausal women.

DPP-4 inhibitors(sitagliptin, linagliptin, alogliptin, saxagliptin) prolong endogenous GLP-1/GIP half-life. Modest A1C drop (0.5-0.9%), weight neutral, essentially no hypoglycemia alone, once-daily, well tolerated, but weaker than GLP-1 RAs and expensive for what they do. Saxagliptin specifically carries an increased HF hospitalization signal, the one class member to avoid in HF. All need renal dose adjustment except linagliptin.

Newly diagnosed T1DM:total daily insulin need is about 0.4-1 units/kg/day (typically cited around 0.5-0.6), split roughly 50% basal / 50% bolus divided across meals. During the honeymoon phase this can fall to 0.1-0.4 units/kg/day, don't be fooled into thinking the disease reversed.

Starting basal in T2DM:10 units once daily or 0.1-0.2 units/kg/day, then self-titrate based on fasting glucose toward the 80-130 mg/dL target.

"Basal plus one" in T2DM(when basal alone isn't controlling postprandial excursions): add ONE bolus injection before the largest meal or the meal with the biggest glucose spike, dosed at 4-5 units or 10% of the basal dose. If A1C is already <8%, consider trimming the basal dose by the same amount you're adding, to avoid stacking hypoglycemia risk. Full multiple daily injections (MDI) add a bolus before every meal instead of just one.

U-500 regular insulinis 5x concentrated and acts as both a basal AND a prandial insulin simultaneously (onset 15 min, peak 4-8 hr, duration 13-24 hr). Reserved for patients needing >200 units/day of extreme insulin resistance. Stop all other insulins when switching to it, and triple-check the doseevery time, concentration errors here are dangerous. Available in pens (5-unit increments) or vials requiring co-dispensed U-500 syringes.

Premixed insulins(like 70/30) combine NPH with either regular or a rapid analog. Naming tells you the mix: brand ending in "-LIN" means NPH + regular, ending in "-LOG" means NPH + a rapid analog. First number in the ratio is the % NPH. Usually dosed BID before breakfast and dinner, with the prolonged NPH peak covering lunch. Downside: you can't independently adjust the basal and bolus components.

Once-weekly basal insulins(icodec, efsitora) are emerging options using extended half-lives (icodec ~8 days via albumin binding, efsitora ~17-19 days as an Fc-fusion protein). Icodec is FDA-approved for T2DM; watch for increased hypoglycemia risk if used off-label in T1DM.