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ENDOCRINOLOGY

DIABETES MELLITUS

Definition (Diabetes Care 2010;33:S62; NEJM 2012;367:542)

•  Hb_A1c ≥6.5 or fasting glc ≥126 mg/dL × 2 or random glc ≥200 mg/dL × 2 (× 1 if severe hyperglycemia and acute metabolic decomp); routine OGTT not recommended (except during pregnancy)

•  Blood glc higher than normal, but not frank DM (“prediabetics,” ~40% U.S. population)

Hb_A1c 5.7–6.4% or impaired fasting glc (IFG): 100–125 mg/dL

Preventing progression to DM: diet & exercise (58% ↓), metformin (31% ↓; NEJM 2002;346:393), TZD (60% ↓; Lancet 2006;368:1096)

Categories

•  Type 1: islet cell destruction; absolute insulin deficiency; ketosis in absence of insulin; prevalence 0.4%; usual onset in childhood but can occur throughout adulthood; ↑ risk if  FHx; HLA associations; anti-GAD, anti-islet cell & anti-insulin autoAb

•  Type 2: insulin resistance + relative insulin ↓; prevalence 8%; onset generally later in life; no HLA associations; risk factors: age,  FHx, obesity, sedentary lifestyle

•  Type 2 DM p/w DKA (“ketosis-prone type 2 diabetes” or “Flatbush diabetes”): most often seen in nonwhite, ± anti-GAD Ab, eventually may not require insulin (Endo Rev 2008;29:292)

•  Mature-Onset Diabetes of the Young (MODY): autosomal dom. forms of DM due to defects in insulin secretion genes; genetically and clinically heterogeneous (NEJM 2001;345:971)

•  Secondary causes of diabetes: exogenous glucocorticoids, glucagonoma (3 Ds = DM, DVT, diarrhea), pancreatic (pancreatitis, hemochromatosis, CF, resection), endocrinopathies (Cushing’s disease, acromegaly), gestational, drugs (protease inhibitors, atypical antipsychotics)

Clinical manifestations

•  Polyuria, polydipsia, polyphagia with unexplained weight loss; can also be asymptomatic

Complications

•  Retinopathy

nonproliferative: “dot & blot” and retinal hemorrhages, cotton-wool/protein exudates

proliferative: neovascularization, vitreous hemorrhage, retinal detachment, blindness

treatment: photocoagulation, surgery, intravitreal bevacizumab injections

•  Nephropathy: microalbuminuria → proteinuria ± nephrotic syndrome → renal failure

diffuse glomerular basement membrane thickening/nodular pattern (Kimmelstiel-Wilson)

usually accompanied by retinopathy; lack of retinopathy suggests another cause

treatment: strict BP control using ACE inhibitors (NEJM 1993;329:1456 & 351:1941; Lancet 1997;349:1787) or ARBs (NEJM 2001;345:851 & 861), low-protein diet, dialysis or transplant

•  Neuropathy: peripheral: symmetric distal sensory loss, paresthesias, ± motor loss

autonomic: gastroparesis, constipation, neurogenic bladder, erectile dysfxn, orthostasis

mononeuropathy: sudden-onset peripheral or CN deficit (footdrop, CN III > VI > IV)

•  Accelerated atherosclerosis: coronary, cerebral and peripheral arterial beds

•  Infections: UTI, osteomyelitis of foot, candidiasis, mucormycosis, necrotizing external otitis

•  Dermatologic: necrobiosis lipoidica diabeticorum, lipodystrophy, acanthosis nigricans

Outpatient screening and treatment goals (Diabetes Care 2012;35:1364)

•  ✓ Hb_A1C q3–6mo, goal <7% for most Pts. Can use goal Hb_A1C ≥7.5–8% if h/o severe hypoglycemia or other comorbidities. Microvascular & macrovascular complications ↓ by strict glycemic control in T1D (NEJM 1993;329:997 & 2005;353:2643) & T2D (Lancet 2009;373:1765; Annals 2009;151:394).

•  Microalbuminuria screening yearly with spot microalbumin/Cr ratio, goal <30 mg/g

•  BP≤130/80 (? ≤140/85, Archives 2012;172:1296), benefit of ACE-I; LDL < 100, TG <150, HDL >40; benefit of statins even w/o overt CAD (Lancet 2003;361:2005 & 2004;364:685); ASA if age >50 () or 60 () or other cardiac risk factors (Circ 2010;121:2694)

•  Dilated retinal exam yearly; comprehensive foot exam qy

Management of hyperglycemia in inpatients (for ICU Pts: see “Sepsis”)

•  Identify reversible causes/exacerbaters (dextrose IVF, glucocorticoids, postop, ↑ carb diet)

•  Dx studies: BG fingersticks (fasting, qAC, qHS; or q6h if NPO), Hb_A1C

•  Treatment goals: avoid hypoglycemia, extreme hyperglycemia (>180 mg/dL)

•  Modification of outPt treatment regimen: In T1D, do not stop basal insulin (can → DKA).

In T2D: stopping oral DM meds generally preferred to avoid hypoglycemia or med interaction (except if short stay, excellent outPt cntl, no plan for IV contrast, nl diet)

•  InPt insulin: can use outPt regimen as guide; if insulin naïve:

total daily insulin = wt (kg) ÷ 2, to start; adjust as needed

give ¹/₂ of total daily insulin as basal insulin in long-acting form to target fasting glc

give other ¹/₂ as short-acting boluses (standing premeal & sliding scale corrective insulin)

•  Discharge regimen: similar to admission regimen unless poor outPt cntl or strong reason for Δ. Arrange early insulin and glucometer teaching, prompt outPt follow-up.

DIABETIC KETOACIDOSIS (DKA)

Precipitants (the I’s)

•  Insulin defic. (ie, failure to take enough insulin); Iatrogenesis (glucocorticoids)

•  Infection (pneumonia, UTI) or Inflammation (pancreatitis, cholecystitis)

•  Ischemia or Infarction (myocardial, cerebral, gut); Intoxication (alcohol, drugs)

Pathophysiology

•  Occurs in T1D (and in ketosis-prone T2D); ↑ glucagon and ↓ insulin

•  Hyperglycemia due to: ↑ gluconeogenesis, ↑ glycogenolysis, ↓ glucose uptake into cells

•  Ketosis due to: insulin deficiency → mobilization and oxidation of fatty acids,

↑ substrate for ketogenesis, ↑ ketogenic state of the liver, ↓ ketone clearance

Clinical manifestations (Diabetes Care 2003;26:S109)

•  Polyuria, polydipsia, & dehydration → ↑ HR, HoTN, dry mucous membranes, ↓ skin turgor

•  N/V, abdominal pain (either due to intra-abdominal process or DKA), ileus

•  Kussmaul’s respirations (deep) to compensate for metabolic acidosis with odor of acetone

•  Δ MS → somnolence, stupor, coma; mortality ~1% even at tertiary care centers

Diagnostic studies

•  ↑ Anion gap metabolic acidosis: can later develop nonanion gap acidosis due to urinary loss of ketones (HCO₃ equivalents) and fluid resuscitation with chloride

•  Ketosis:  urine and serum ketones (predominant ketone is β-OH-butyrate, but acetoacetate measured by assay; urine ketones may be  in fasting normal Pts)

•  ↑ Serum glc; ↑ BUN & Cr (dehydration ± artifact due to ketones interfering w/ some assays)

•  Hyponatremia: corrected Na = measured Na + [2.4 × (measured glc −100)/100]

•  ↓ or ↑ K (but even if serum K is elevated, usually total body K depleted); ↓ total body phos

•  Leukocytosis, ↑ amylase (even if no pancreatitis)

HYPEROSMOLAR HYPERGLYCEMIC STATE

Definition, precipitants, pathophysiology (Diabetes Care 2003;26:S33)

•  Extreme hyperglycemia (w/o ketoacidosis) + hyperosm. + Δ MS in T2D (typically elderly)

•  Precip same as for DKA, but also include dehydration and renal failure

•  Hyperglycemia → osmotic diuresis → vol depletion → prerenal azotemia → ↑ glc, etc.

Clinical manifestations & dx studies (Diabetes Care 2006;29[12]:2739)

•  Volume depletion and Δ MS

•  ↑ serum glc (usually >600 mg/dL) and ↑ meas. serum osmolality (>320 mOsm/L) effective Osm = 2 × Na (mEq/L) + glc (mg/dL)/18

•  No ketoacidosis; usually ↑ BUN & Cr; [Na] depends on hyperglycemia & dehydration

Treatment (r/o possible precipitants; ~15% mortality due to precipitating factors)

•  Aggressive hydration: initially NS, then ¹/₂ NS, average fluid loss up to 8–10 L

•  Insulin (eg, 10 U IV followed by 0.05–0.1 U/kg/h)

HYPOGLYCEMIA

Clinical manifestations (glucose <~55 mg/dL)

•  CNS: headache, visual Δs, Δ MS, weakness, seizure, LOC (neuroglycopenic sx)

•  Autonomic: diaphoresis, palpitations, tremor (adrenergic sx)

Etiologies in diabetics

•  Excess insulin, oral hypoglycemics, missed meals, renal failure (↓ insulin & SU clearance)

•  β-blockers can mask adrenergic symptoms of hypoglycemia

Etiologies in nondiabetics

•  ↑ insulin: exogenous insulin, sulfonylureas, insulinoma, anti-insulin antibodies

•  ↓ glucose production: hypopituitarism, adrenal insufficiency, glucagon deficiency, hepatic failure, renal failure, CHF, alcoholism, sepsis, severe malnutrition

•  ↑ IGF-II: non-islet tumor

•  Postprandial, esp. postgastrectomy or gastric bypass: excessive response to glc load

•  Low glc w/o sx can be normal

Evaluation in nondiabetics (J Clin Endocrinol Metab 2009;94:709)

•  If clinically ill: take measures to avoid recurrent hypoglycemia; ✓ BUN, Cr, LFTs, TFTs, prealbumin; IGF-I/IGF-II ratio when appropriate

•  If otherwise healthy: 72-h fast w/ monitored blood glc; stop for neuroglycopenic sx

•  At time of hypoglycemia: insulin, C peptide (↑ w/ insulinoma and sulfonylureas, ↓ w/ exogenous insulin), β-OH-butyrate, sulfonylurea levels

•  At end of fast, give 1 mg glucagon IV and measure response of plasma glc before feeding

Treatment

•  Glucose tablets, paste, fruit juice are first-line Rx for Pts who can take POs

•  If IV access available, give 25–50 g of D₅₀ (50% dextrose)

•  If no IV, can give glucagon 0.5–1 mg IM or SC (side effect: N/V)