Diabetes Mellitus

Definition (Owbetes Core 2003:26:S33)

• Fasting glc >126 mg dl or rand, glc >200 mg dl x 2 or 75 gOGTTw 2-h glc >200 mg dl

• Blood glc higher than normal, but not frank diabetes:

Impaired fasting glc (IFG) 100-125 mg dl

Impaired glc tolerance (IGT): 2-h glc after 75 g OGTT 140-199 mg dl

• ? T HbAic (no accepted criterion yet) Categories

• Type 1: islet cell destruction; absolute insulin deficiency; ketosis in absence of insulin prevalence 0.4%; usual onset in childhood; T risk if © FHx; HLA associations anti-GAD, anti-islet cell & anti-insulin autoantibodies

• Type 2: insulin resistance + relative insulin deficiency (prevent ketosis but not t glc)

insulin resistance -» T glc — 1 insulin secretion . pancreatic failure — overt diabetes prevalence 8%; onset in later life: TT risk if © FHx; no HLA associations risk factors: age. race. FHx. obesity, sedentary lifestyle, metabolic abnormalities

• Type 2 DM p/w DKA ("Flatbush Diabetes"): most often seen in young blacks. anti-GAD

neg. often do not require insulin following Rx of DKA {Dnbetei 1994*3:741)

• Mature-Onset Diabetes of the Young (MODY): autosomal dominant inherited form of DM due to defects in insulin secretion genes; occurs in lean young adults who do not normally require insulin inejm 2001:345:971)

• Secondary causes of diabetes: exogenous or endogenous glucocorticoids.glucagonoma

(3 D's = DM. DVT. diarrhea), pancreatic (pancreatitis, hemochromatosis. CF. resection) Clinical manifestations

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

Diabetes Treatment Options

Diet

Type 1:ADA diet;Type 2: wt reduction diet + exercise

Metformin

. hepatic gluconeogenesis. J HbAic 1.5% Wt neutral. N V & diarrhea, rare lactic acidosis Contraindic. in renal or liver failure

Consider first-line Rx w lifestyle mod. for all DM2 w HbAic ^7%

Sulfonylureas (SU)

T insulin secretion, J HbAic 1.5% Hypoglycemia, wt gain

Thiazolidinediones (TZD)

f insulin Se in adipose & muscle (PPAR^ agonist) i HbAic 0.5-1.4%

Wt gain, hepatotoxicity. fluid retention & CHF. > t Ml Contraindic. in liver disease and NYHA lll-IV, monitor LFTs

Glinides

T insulin secretion. 1 HbAic 1.5% Hypoglycemia (but less than w SU). wt gain

Exenitide

' glc-depend insulin secretion (GLP-1 agonist). 1 HbAic 0.5%

To be used in combination with an oral agent

i.-glucosidasc inhibitor

i intestinal CHO absorption, i HbAic 0.5-0.8% Gl distress (gas).

Pramlintide

Delays gastric emptying & i glucagon. 1 HbAic 0.5% To be used as adjunctive Rx w insulin in DM1 or DM2

DPP-4 inhibitor

Blocks degrad. of GLP-1 & GIP — T insulin, i HbAic 0.5%

Insulin

(Additional DM1 options: insulin pump, pancreatic or islet cell transplant)

i Hb*ic 1.5-2.5%; hypoglycemia, wt gain Generally combine intermed. long-acting (NPH or glargine) and short rapid-acting (regular or lispro) insulin. Consider sorting if mono oral Rx not adequate (espec if T HbAn high) and definitely start if combo oral Rx not adequate.

(/AMA 2002:287:360.373: Owbetotojw 2006:49:1711)

Insulin Preparations

Preparation

Onset

Peak

Duration

Side effects Comments

Lispro. aspart

5-15 min

60-90 mln

2-4 h

Give immediately before mea\

Regular

30-60 min

2-4 h

5-8 h

Give 30 min before meal

NPH

1-2 h

4-8 h

12-18 h

Can cause protamine Ab prod

Glargine

2 h

No peak

20-24 h

Once daily (AM or PM)

Inhaled

5-15 min

-2-4 h

6-8 h

Causes cough, variable absorp

(NEJM 2005:352:174)

(NEJM 2005:352:174)

Complications

• Retinopathy non-proliferatrve: "dot & blot" and retinal hemorrhages, cotton wool protein exudates proliferative: neovascularization, vitreous hemorrhage, retinal detachment, blindness treatment; photocoagulation

• 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: Stria BP control. ACE inhibitors (NEfM 1993:329:1456; Lancef 1997:349:1787) & ARBs (NEfM 2001:345:851.861). low-protein diet, dialysis, or transplant

• Neuropathy symmetric peripherah symmetric distal sensory loss, paresthesias, r motor loss autonomic: gastroparesis. neurogenic bladder, impotence, orthostatic hypotension mononeuropothy. sudden onset peripheral or CN deficit (footdrop, CN III > VI > IV)

• Accelerated atherosclerosis: coronary, cerebral, and peripheral arterial beds

• Infections: candidiasis, mucormycosis, necrotizing external otitis

• Dermatologie: necrobiosis lipoidica diabeticorum, lipodystrophy, acanthosis nigricans

Outpatient screening and treatment goals (Dfctwtn Con 2006:2954)

• / Hbxic q3-6mos. goal <7%; microvascular & macrovascular complications i by stria glycemic control, in DM1 (DCCT. NEJM 1993:329:997 & 2005:353.2643) & DM2 (UKPDS. Lancet 1998:352*37)

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

• BP <130 80; LDL < 100. TG <150. HDL -40; benefit of statins in all diabetics even w o overt CAD (Lancet 2003:361:2005 & 2004:364 685); ASA if age >40 or other cardiac risk factors

• Dilated retinal exam yearly, podiatrist yearly at a minimum

Diabetic Ketoacidosis (DKA)

• Insulin deficiency (ie. failure to take enough insulin)

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

• Ischemia or Infarction (myocardial, cerebral, gut)

• Intoxication (alcohol, drugs)

• latrogenesis glucocorticoids, thiazides

Pathophysiology

• Occurs in type 1 diabetics (and rarely in type 2 diabetics)

• t glucagon and 1 Insulin

• Hyperglycemia due to: î gluconeogenesis. t glycogenolysis. 1 glucose uptake into cells

• Ketosis due to: inability to utilize glucose — mobilization and oxidation of fatty acids.

î substrate for ketogenesis. Î ketogenic state of the liver. I ketone clearance

• Mortality -1% when Pts cared for in tertiary care centers

Clinical manifestations (0w6ete» Core 2003.265109)

• Polyuria, polydipsia, and dehydration

• Dehydration -» î HR. hypotension, dry mucous membranes. I skin turgor

• Nausea, vomiting, abdominal pain (either due to intra-abdominal process or DKA). ileus

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

Diagnostic studies

• t anion gap metabolic acidosis: can later develop nonanion gap acidosis due to urinary loss of ketones (HCOj equivalents) and fluid resuscitation with chloride

• Ketosis: • urine and serum ketones (acetoacetate measured, but predominant ketone is (3-OH-butyrate; urine ketones may be © in fasting normal individuals)

• t BUN and Cr (dehydration ^ artifact due to ketones interfering with some Cr assays)

• Pseudohyponatremia: corrected Na - measured Na + [(2.4 > (measured glucose - 100)]

• I or t K (but even if serum K is elevated, usually total body K depleted)r. 1 total body phos

• Leukocytosis, t amylase (even if no pancreatitis)

Typical DKA "Flow sheet" Setu Time VS UOP pH HCOj AG Ketones Glc

K PO, IVF Insulin

Note: Mam ketone produced is (i-OH-butyrate (0OHB). but ketone meosured is ocetoocetote (Ac-Ac). As DKA a treoted, pOHB -»Ac-Ac. .*. AC con decrease while meosured ketones can increase.

Treatment of DKA

Rule out possible précipitants

Infection, intra-abdominal process. Ml, etc.

Aggressive hydration

NS 10-14 ml kg h, tailor to dehydration & CV status

Insulin

10 U IV push followed by 0.1 U kg h Continue insulin drip until AG normal If glc - 250 and AG still high - add dextrose to IVF

and continue insulin to metabolize ketones AG normal - SC insulin (overlap IV & SC 2-3 h)

Electrolyte repletion

K: add 20-40 mEq L IVF if serum K <4.5 insulin promotes K entry into cells — I serum K careful K repletion in Pts with renal failure HCOj: replete if pH <7 or if cardiac instability PO«: replete if <1

Hyperosmolar Hyperglycemic State

Definition, Précipitants, Pathophysiology (0m6«« Com 2003:26:533)

• Extreme hyperglycemia (w o ketoacidosis) • hyperosm. ► A MS in DM2 (typically elderly)

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

• Hyperglycemia -» osmotic diuresis -» dehydration prerenal azotemia Î glc. etc.

Clinical manifestations & Diagnostic studies

• Dehydration and A MS

• t serum glc (usually -600 mg dl) and Î serum osmolality (usually >350 mOsm L)

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

Treatment (r o possible précipitants; -15% mortality due to precipitating factors)

• Aggressive hydration: initially NS. average fluid loss up to 8-10 L

• Insulin (eg. 10 U IV followed by 0.05-0.1 U kg h)

Glycemic Control in Critically III Patients 2006:3551903»

Tight glycemic control w IV insulin (glc 80-110) confers survival benefit in critically ill surgical Pts; in MICU Pts. some benefit on morbidity and a mortality benefit for those in ICU >3 d (NE/M 2001:345:1359 & 2006:354:449)

Benefit of normoglycemia in acute Ml less well-established

Goal for ICU and acute Ml Pts is maintaining glc « 140 w avoidance of hypoglycemia and resultant adrenergic surge; standardized insulin infusion protocols should be used

Hypoglycemia

Etiologies in diabetics

• Excessive insulin, oral hypoglycemics, missed meals, renal failure (J insulin & SU

clearance), hypothyroidism

• p-blockers can mask symptoms of hypoglycemia

Etiologies in nondiabetics

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

• I glucose production: hypopituitarism, adrenal insufficiency, glucagon deficiency.

hepatic failure, renal failure, alcoholism, sepsis

• Postprandial, especially postgastrectomy: excessive response to glucose load

Clinical manifestations (glucose < -55 mg dl)

• CNS: headache, visual As. A MS, weakness (neuroglycopenic sx)

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

Evaluation [NEJM 1995:332:1144)

• 72-h fast with monitored blood glucoses; stop for neuroglycopenic sx

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

• At time of hypoglycemia: insulin, C peptide (i with insulinoma and sulfonylureas, i with exogenous insulin). [J-OH-butyrate. sulfonylurea levels, and IGF-II Treatment

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

• If IV access available, give 25-50 g of D» (50% dextrose)

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

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