Cellulitis - NEJM Review

Clues:

• Erysipela is a type of cellulitis, but must be diferenciated because of the complications
• In diabetic foot, the best treatment is Ampicilline-Sulbactam plus Clindamicine
• Skin biopsy lacks of sensibility, but must be performed
• In clinical practice, it is very important to follow the rapid progressive cellulitis (e.g. pen mark), to determinate the progression and do diferencial diagnosis with necrotizing fascitis.

Cellulitis is an acute, spreading pyogenic inflammation of the dermis and subcutaneous

tissue, usually complicating a wound, ulcer, or dermatosis. The area, usually on the

leg, is tender, warm, erythematous, and swollen. It lacks sharp demarcation from uninvolved

skin. Erysipelas is a superficial cellulitis with prominent lymphatic involvement,

presenting with an indurated, “peau d’orange” appearance with a raised border

that is demarcated from normal skin. The distinctive features, including the anatomical

location of cellulitis and the patient’s medical and exposure history, should guide

appropriate antibiotic therapy

Crepitant cellulitis is produced by either clostridia or non–spore-forming anaerobes (bacteroides species, peptostreptococci, and peptococci) — either alone or mixed with facultative bacteria, particularly Escherichia coli, klebsiella, and aeromonas. Gangrenous cellulitis produces necrosis of the subcutaneous tissues and overlying skin. Skin necrosis may complicate conventional cellulitis or may occur with distinctive clinical features (including necrotizing cutaneous mucormycosis in immunocompromised patients

Specific pathogens are suggested when infection follows exposure to seawater ( Vibrio vulnificus ), fresh water ( Aeromonas hydrophila ), or quacultured fish ( Streptococcus iniae)

Occasionally, cellulitis may be caused by the spread of subjacent osteomyelitis. Rarely, infection may emerge as apparent cellulitis, sometimes distant from the initial site. Crepitant cellulitis on the left thigh, for instance, might be a manifestation of a colonic diverticular abscess.

Cellulitis infrequently occurs as a result of bacteremia. Uncommonly, pneumococcal cellulitis occurs on the face or limbs in patients with diabetes mellitus, alcohol abuse, systemic lupus erythematosus, the nephrotic syndrome, or a hematologic cancer.Meningococcal cellulitis occurs rarely, although it can affect both children (periorbital cellulitis) and adults (cellulitis on an extremity). 11 Bacteremic cellulitis due to V. vulnificus with prominent hemorrhagic bullae may follow the ingestion of raw oysters by patients with cirrhosis, hemochromatosis.

Cellulitis caused by other gram-negative organisms (e.g., E. coli ) usually occurs through a cutaneous source in an immunocompromised patient but can also develop through

Bacteremia 14 ; it sometimes follows Pseudomonas aeruginosa bacteremia in patients with neutropenia. In immunocompromised persons, less common opportunistic pathogens (e.g.,

Helicobacter cinaedi in patients with human immunodeficiency virus infection; Cryptococcus neoformans; and fusarium, proteus, and pseudomonas species) have also been associated

with bloodborne cellulitis.

However, data from five series using needle aspiration have elucidated common pathogens.

Among 284 patients, a likely pathogen was identified in 29 percent. Gram-positive microorganisms (mainly Staphylococcus aureus, group A or B streptococci, viridans streptococci, and Enterococcus faecalis ) accounted for 79 percent of cases.

A small study in children demonstrated higher yields when needle aspirates were obtained from the point of maximal inflammation than when they were obtained from the leading edge.

These data indicate that antimicrobial therapy for cellulitis in immunocompetent hosts should be focused primarily on gram-positive cocci.

Broader coverage is warranted in patients with diabetes. Among 96 leg-threatening foot infections (including cellulitis) in patients with diabetes, the main potential pathogens recovered from deep wounds or débrided tissue were gram-positive aerobes including S. aureus,

enterococci, and streptococci (in 56 percent of cases); gram-negative aerobes including proteus, E. coli, klebsiella, enterobacter, acinetobacter, and P. aeruginosa (in 22 percent);

and anaerobes including bacteroides and peptococcus (in 22 percent). 31

USUAL CELLULITIS TREATMENT

SPECIFIC CELLULITIS TREATMENT

This broad range of microorganisms should also be considered as potential pathogens in cellulitis that occurs as a complication of decubitus ulcers. Bacteremia is uncommon in cellulitis: among 272 patients, initial blood cultures were positive in 4 percent

In contrast, blood cultures are indicated in patients who have cellulitis superimposed on lymphedema.. attributable to the preexisting lymphedema and the infecting bacterial species. Blood cultures are also warranted in patients with buccal or periorbital cellulitis, in patients in whom a salt-water or fresh-water source of infection is likely (Table 3), and in patients with chills and high fever, which suggest bacteremia.

study involving 17 patients with suspected necrotizing fasciitis, 11 cases were ultimately confirmed to be necrotizing fasciitis (at surgery or, in 1 case, on autopsy), and 6 were confirmed to be cellulitis on the basis of the clinical course 33

; on MRI, all 11 cases of necrotizing fasciitis were identified (100 percent sensitivity), but 1 of the 6 cases of cellulitis was misdiagnosed (for a specificity of 86 percent). The criteria for identifying necrotizing fasciitis on MRI include the involvement of deep fasciae, as evidenced

by fluid collection, thickening, and enhancement with contrast material.

But ultrasonography can be helpful in detecting the subcutaneous accumulation of pus as a complication of cellulitis and can aid in guiding aspiration.

Diabetic foot infections involve multiple potential pathogens, and broad antimicrobial coverage

is required.

31

Ampicillin–sulbactam and imipenem– cilastatin were shown in a randomized, double-blind trial to have similar cure rates in this setting (81 percent vs. 85 percent), but the former combination was more cost effective. randomized, double-blind trial of treatment of complicated skin and soft-tissue infections in 819 hospitalized adults,

42

44 percent of whom had cellulitis. The cure rates were 89 percent for linezolid and 86 percent for oxacillin. Clinically relevant pathogens isolated from contiguous sites included S. aureus

(in 35 percent), group A streptococci (in 11 percent), and group B streptococci (in 27 percent),

but infections due to methicillin-resistant S. aureus were excluded. A trial comparing linezolid and vancomycin in the treatment of adults with methicillin- resistant S. aureus infections, including 175 skin and soft-tissue infections, found similar cure rates (79 percent with linezolid and 73 percent with vancomycin), but cellulitis accounted for only 13 percent of these infections.

ancillary measures

The local care of cellulitis involves the elevation and immobilization of the involved limb to reduce swelling and cool sterile saline dressings to remove purulence from any open lesion. Interdigital dermatophytic infections should be treated with a topical antifungal agent until they have been cleared. Such lesions may provide ingress for infecting bacteria.

Several classes of topical antifungal agents are effective in clearing up fungal infection when

applied one to two times daily; these include imidazoles (clotrimazole and miconazole), allylamines (terbinafine), and substituted pyridones (ciclopirox olamine).

44

Observational data suggest that after the successful treatment of such dermatophytic infections,

the subsequent prompt use of topical antifungal agents at the earliest evidence of recurrence

(or prophylactic application once or twice Patients with peripheral edema are predisposed

to recurrent cellulitis. Support stockings, good skin hygiene, and prompt treatment of tinea pedis can prevent recurrences. In patients who, despite these measures, continue to have frequent episodes of cellulitis or erysipelas, the prophylactic use of penicillin G (250 to 500 mg orally twice daily) may prevent additional episodes; if the patient is allergic to penicillin, erythromycin (250 mg orally once or twice daily) may be used

Reference

Cellulitis

Chronic complications of diabetes

The risk of chronic complications increases as a function of the duration of hyperglycemia; they usually become apparent in the second decade of hyperglycemia. Since type 2 DM often has a long asymptomatic period of hyperglycemia, many individuals with type 2 DM have complications at the time of diagnosis. For example, despite long-standing DM, some individuals never develop nephropathy or retinopathy. Many of these patients have glycemic control that is indistinguishable from those who develop microvascular complications, suggesting that there is a genetic susceptibility for developing particular complications

Mechanism of hyper glicemia

One theory is that increased intracellular glucose leads to the formation of advanced glycosylation end products (AGEs) via the nonenzymatic glycosylation of intra- and extracellular proteins. Nonenzymatic glycosylation results from the interaction of glucose with amino groups on proteins. AGEs have been shown to cross-link proteins (e.g., collagen, extracellular matrix proteins), accelerate atherosclerosis, promote glomerular dysfunction, reduce nitric oxide synthesis, induce endothelial dysfunction, and alter extracellular matrix composition and structure.

Intracellular glucose is predominantly metabolized by phosphorylation and subsequent glycolysis, but when increased, some glucose is converted to sorbitol by the enzyme aldose reductase. Increased sorbitol concentration alters redox potential, increases cellular osmolality, generates reactive oxygen species, and likely leads to other types of cellular dysfunction.

A third hypothesis proposes that hyperglycemia increases the formation of diacylglycerol leading to activation of protein kinase C (PKC). Among other actions, PKC alters the transcription of genes for fibronectin, type IV collagen, contractile proteins, and extracellular matrix proteins in endothelial cells and neurons

A fourth theory proposes that hyperglycemia increases the flux through the hexosamine pathway, which generates fructose-6-phosphate, a substrate for O-linked glycosylation and proteoglycan production. The hexosamine pathway may alter function by glycosylation of proteins such as endothelial nitric oxide synthase or by changes in gene expression of transforming growth factor (TGF-) or plasminogen activator inhibitor-1 (PAI-1).

Vascular endothelial growth factor A (VEGF-A) is increased locally in diabetic proliferative retinopathy and decreases after laser photocoagulation. TGF- is increased in diabetic nephropathy and stimulates basement membrane production of collagen and fibronectin by mesangial cells. A possible unifying mechanism is that hyperglycemia leads to increased production of reactive oxygen species or superoxide in the mitochondria; these compounds may activate all four of the pathways described above.

One of the major findings of the UKPDS was that strict blood pressure control significantly reduced both macro- and microvascular complications.

Retinopathy

The gravity of this problem is highlighted by the finding that individuals with DM are 25 times more likely to become legally blind than individuals without DM. Diabetic retinopathy is classified into two stages: nonproliferative and proliferative. Nonproliferative diabetic retinopathy usually appears late in the first decade or early in the second decade of the disease and is marked by retinal vascular microaneurysms, blot hemorrhages, and cotton wool spots (Fig. 338-9). Mild nonproliferative retinopathy progresses to more extensive disease, characterized by changes in venous vessel caliber, intraretinal microvascular abnormalities, and more numerous microaneurysms and hemorrhages. The pathophysiologic mechanisms invoked in nonproliferative retinopathy include loss of retinal pericytes, increased retinal vascular permeability, alterations in retinal blood flow, and abnormal retinal microvasculature, all of which lead to retinal ischemia. The appearance of neovascularization in response to retinal hypoxia is the hallmark of proliferative diabetic retinopathy (Fig. 338-9). These newly formed vessels appear near the optic nerve and/or macula and rupture easily, leading to vitreous hemorrhage, fibrosis, and ultimately retinal detachment. Fluorescein angiography is useful to detect macular edema, which is associated with a 25% chance of moderate visual loss over the next 3 years. Duration of DM and degree of glycemic control are the best predictors of the development of retinopathy; hypertension is also a risk factor. Laser photocoagulation is very successful in preserving vision. Proliferative retinopathy is usually treated with panretinal laser photocoagulation, whereas macular edema is treated with focal laser photocoagulation.

Nephropathy

Diabetic nephropathy is the leading cause of ESRD in the United States and a leading cause of DM-related morbidity and mortality. Both microalbuminuria and macroalbuminuria in individuals with DM are associated with increased risk of cardiovascular disease. Individuals with diabetic nephropathy commonly have diabetic retinopathy.

Like other microvascular complications, the pathogenesis of diabetic nephropathy is related to chronic hyperglycemia. Smoking accelerates the decline in renal function. Because only 20–40% of patients with diabetes develop diabetic nephropathy, additional susceptibility factors remain unidentified. One known risk factor is a family history of diabetic nephropathy.

Glomerular hyperperfusion and renal hypertrophy occur in the first years after the onset of DM and are associated with an increase of the glomerular filtration rate (GFR). During the first 5 years of DM, thickening of the glomerular basement membrane, glomerular hypertrophy, and mesangial volume expansion occur as the GFR returns to normal. After 5–10 years of type 1 DM, ~40% of individuals begin to excrete small amounts of albumin in the urine. Microalbuminuria is defined as 30–300 mg/d in a 24-h collection or 30–300 mg/mg creatinine in a spot collection (preferred method). Although the appearance of microalbuminuria in type 1 DM is an important risk factor for progression to overt proteinuria (>300 mg/d), only ~50% of individuals progress to macroalbuminuria over the next 10 years. In some individuals with type 1 diabetes and microalbuminuria of short duration, the microalbuminuria regresses. Once macroalbuminuria is present, there is a steady decline in GFR, and ~50% of individuals reach ESRD in 7–10 years. Once macroalbuminuria develops, blood pressure rises slightly and the pathologic changes are likely irreversible. Some individuals with type 1 or type 2 DM have a decline in GFR in the absence of micro- or macroalbuminuria and this is the basis for assessing the GFR on an annual basis using serum creatinine. Finally, it should be noted that albuminuria in type 2 DM may be secondary to factors unrelated to DM, such as hypertension, congestive heart failure (CHF), prostate disease, or infection.

Type IV renal tubular acidosis (hyporeninemic hypoaldosteronism) may occur in type 1 or 2 DM. These individuals develop a propensity to hyperkalemia, which may be exacerbated by medications [especially angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs)]. Patients with DM are predisposed to radiocontrast-induced nephrotoxicity. Risk factors for radiocontrast-induced nephrotoxicity are preexisting nephropathy and volume depletion.

The recommended strategy for detecting microalbuminuria is outlined in Fig. 338-11 and includes annual measurement of the serum creatinine to estimate GFR.

Screening for microalbuminuria should be performed in patients with type 1 diabetes for more tan 5 years, in patients with type 2 diabetes, and during pregnancy

Non-diabetes-related conditions that might increase microalbuminuria are urinary tract infection, hematuria, heart failure, febrile illness, severe hyperglycemia, severe hypertension, and vigorous exercise

During the phase of declining renal function, insulin requirements may fall as the kidney is a site of insulin degradation. Furthermore, many glucose-lowering medications (sulfonylureas and metformin) are contraindicated in advanced renal insufficiency. pressure should be maintained at <130/80 style="background: yellow none repeat scroll 0% 0%; -moz-background-clip: -moz-initial; -moz-background-origin: -moz-initial; -moz-background-inline-policy: -moz-initial;">macroalbuminuria.

The ADA suggests modest restriction of protein intake in diabetic individuals with microalbuminuria (0.8 g/kg per day) or macroalbuminuria (<0.8>, which is the adult Recommended Daily Allowance, or ~10% of the daily caloric intake).

Neuropathy

Additional risk factors are BMI (the greater the BMI, the greater the risk of neuropathy) and smoking. The presence of cardiovascular disease, elevated triglycerides, and hypertension is also associated with diabetic peripheral neuropathy. The ADA recommends screening for distal symmetric neuropathy beginning with the initial diagnosis of diabetes and screening for autonomic neuropathy 5 years after diagnosis of type 1 DM and at the time of diagnosis of type 2 DM. All individuals with diabetes should then be screened annually for both forms of neuropathy.

Polyneuropathy/Mononeuropathy

The most common form of diabetic neuropathy is distal symmetric polyneuropathy. It most frequently presents with distal sensory loss, but up to 50% of patients do not have symptoms of neuropathy. Hyperesthesia, paresthesia, and dysesthesia also may occur. Any combination of these symptoms may develop as neuropathy progresses. Symptoms may include a sensation of numbness, tingling, sharpness, or burning that begins in the feet and spreads proximally. Neuropathic pain develops in some of these individuals, occasionally preceded by improvement in their glycemic control. Pain typically involves the lower extremities, is usually present at rest, and worsens at night. Both an acute (lasting <12>. As diabetic neuropathy progresses, the pain subsides and eventually disappears, but a sensory deficit in the lower extremities persists. Physical examination reveals sensory loss, loss of ankle reflexes, and abnormal position sense.

Diabetic polyradiculopathy is a syndrome characterized by severe disabling pain in the distribution of one or more nerve roots. It may be accompanied by motor weakness. Intercostal or truncal radiculopathy causes pain over the thorax or abdomen. Involvement of the lumbar plexus or femoral nerve may cause severe pain in the thigh or hip and may be associated with muscle weakness in the hip flexors or extensors (diabetic amyotrophy).

Mononeuropathy (dysfunction of isolated cranial or peripheral nerves) is less common than polyneuropathy in DM and presents with pain and motor weakness in the distribution of a single nerve. A vascular etiology has been suggested, but the pathogenesis is unknown. Involvement of the third cranial nerve is most common and is heralded by diplopia. Physical examination reveals ptosis and ophthalmoplegia with normal pupillary constriction to light. Sometimes other cranial nerves IV, VI, or VII (Bell's palsy) are affected. Peripheral mononeuropathies or simultaneous involvement of more than one nerve (mononeuropathy multiplex) may also occur.

Autonomic

Autonomic neuropathies affecting the cardiovascular system cause a resting tachycardia and orthostatic hypotension. Reports of sudden death have also been attributed to autonomic neuropathy. Gastroparesis and bladder-emptying abnormalities are often caused by the autonomic neuropathy seen in DM (discussed below). Hyperhidrosis of the upper extremities and anhidrosis of the lower extremities result from sympathetic nervous system dysfunction. Anhidrosis of the feet can promote dry skin with cracking, which increases the risk of foot ulcers. Autonomic neuropathy may reduce counterregulatory hormone release, leading to an inability to sense hypoglycemia appropriately (hypoglycemia unawareness).

Diabetes Mellitus

For example, individuals with type 2 DM may return to the impaired glucose tolerance category with weight loss
These values do not apply to the diagnosis of gestational DM.
It is estimated that between 5 and 10% of individuals who develop DM after age 30 have type 1 DM.
In 2005, the prevalence of DM in the United Sates was estimated to be 0.22% in those <20>20 years. In individuals >60 years, the prevalence of DM was 20.9%. The prevalence is similar in men and women throughout most age ranges (10.5% and 8.8% in individuals >20 years) but is slightly greater in men >60 years
In 2005, the CDC estimated that the prevalence of DM in the United States (age > 20 years) was 13.3% in African Americans, 9.5% in Latinos, 15.1% in Native Americans (American Indians and Alaska natives), and 8.7% in non-Hispanic whites. Individuals belonging to Asian-American or Pacific-Islander ethnic groups in Hawaii are twice as likely to have diabetes compared to non-Hispanic whites.
DM is defined as the level of glycemia at which diabetes-specific complications occur rather than on deviations from a population-based mean
Criterios Dx de DM
• Symptoms of diabetes plus random blood glucose concentration >11.1 mmol/L (200 mg/dL)aor
• Fasting plasma glucose >7.0 mmol/L (126 mg/dL)bor
• Two-hour plasma glucose >11.1 mmol/L (200 mg/dL) during an oral glucose tolerance testc
Glucose tolerance is classified into three categories based on the FPG (Fig. 338-1): (1) FPG <>= 5.6–6.9 mmol/L (100–125 mg/dL) is defined as IFG; and (3) FPG >7.0 mmol/L (126 mg/dL) warrants the diagnosis of DM. Based on the OGTT, IGT is defined as plasma glucose levels between 7.8 and 11.1 mmol/L (140 and 199 mg/dL) and diabetes is defined as a glucose > 11.1 mmol/L (200 mg/dL) 2 h after a 75-g oral glucose load.
Some individuals have both IFG and IGT. Individuals with IFG and/or IGT, recently designated pre-diabetes by the American Diabetes Association (ADA), are at substantial risk for developing type 2 DM (25–40% risk over the next 5 years) and have an increased risk of cardiovascular disease.
The current criteria for the diagnosis of DM emphasize that the FPG is the most reliable and convenient test for identifying DM in asymptomatic individuals. A random plasma glucose concentration >11.1 mmol/L (200 mg/dL) accompanied by classic symptoms of DM (polyuria, polydipsia, weight loss) is sufficient for the diagnosis of DM (Table 338-2). Oral glucose tolerance testing, although still a valid means for diagnosing DM, is not recommended as part of routine care. the A1C is not currently recommended to diagnose diabetes.
Screening: ADA recommends screening all individuals >45 years every 3 years and screening individuals at an earlier age if they are overweight [body mass index (BMI) > 25 km/m2] and have one additional risk factor for diabetes
Risk factors (10)
Family history of diabetes (i.e., parent or sibling with type 2 diabetes)
Obesity (BMI >25 kg/m2) (sobrepeso)
Habitual physical inactivity
Race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander)
Previously identified IFG or IGT
History of GDM or delivery of baby >4 kg (>9 lb)
Hypertension (blood pressure >140/90 mmHg)
HDL cholesterol level <35>250 mg/dL (2.82 mmol/L)
Polycystic ovary syndrome or acanthosis nigricans
History of vascular disease

Insuline: Insulin is produced in the beta cells of the pancreatic islets. It is initially synthesized as a single-chain 86-amino-acid precursor polypeptide, preproinsulin. Subsequent proteolytic processing removes the aminoterminal signal peptide, giving rise to proinsulin. Proinsulin is structurally related to insulin-like growth factors I and II, which bind weakly to the insulin receptor. Cleavage of an internal 31-residue fragment from proinsulin generates the C peptide and the A (21 amino acids) and B (30 amino acids) chains of insulin, which are connected by disulfide bonds. The mature insulin molecule and C peptide are stored together and cosecreted from secretory granules in the beta cells. Because the C peptide is cleared more slowly than insulin, it is a useful marker of insulin secretion and allows discrimination of endogenous and exogenous sources of insulin in the evaluation of hypoglycemia

Glut 2 secrecion insulin insulin estimula expression glut 4
Glucose phosphorylation by glucokinase is the rate-limiting step that controls glucose-regulated insulin secretion. Further metabolism of glucose-6-phosphate via glycolysis generates ATP, which inhibits the activity of an ATP-sensitive K+ cannel. Inhibition of this K+ channel induces beta cell membrane depolarization, which opens voltage-dependent calcium channels (leading to an influx of calcium), and stimulates insulin secretion. Glucagon-like peptide 1 (GLP-1), the most potent incretin, is released from L cells in the small intestine and stimulates insulin secretion only when the blood glucose is above the fasting level. Incretin analogues, such as exena-tide, are being used to enhance endogenous insulin secretion.
Once insulin is secreted into the portal venous system, ~50% is degraded by the liver.
Descrito hace más de 40 años, se debe a la acción de 2 hormonas gastrointestinales conocidas como GLP-1 (glucagon-like peptide-1,) y GIP (glucose-dependent insulinotropic polypeptide). GLP-1 es secretado por la células L situadas a nivel del íleon y colon, mientras que GIP es liberado a partir de las células K localizadas en el duodeno y yeyuno. Las incretinas, especialmente el GLP-1, tienen un efecto dual al incrementar la secreción de insulina y suprimir la secreción de glucagón de forma glucosa dependiente. Este efecto se halla presente en la diabetes tipo 2, aunque disminuido. Ambas hormonas, GLP-1 y GIP son inactivadas rápidamente (2-3 min) por la enzima dipeptidil peptidasa-4 (DPP-IV), presente en la circulación (forma soluble) y en diversos tejidos. La infusión iv. continua de GLP-1 disminuye la concentración plasmática de glucosa en ayunas y tras la ingesta.
Para aumentar el efecto de GLP-1 en pacientes con diabetes tipo 2 se han utilizado dos estrategias distintas: (1) utilizar análogos de GLP-1 (incretín-miméticos), como exenatide (Byetta®, comercializado en EEUU) o liraglutide, resistentes a la acción de GLP-1, que se administran 1-2 veces/día por vía sc., o (2) inhibir la enzima DPP-IV para incrementar los niveles de GLP-1 de forma fisiológica (potenciadores del efecto incretina, PEI).
DM1: In the majority, immunologic markers appear after the triggering event but before diabetes becomes clinically overt. Features of diabetes do not become evident until a majority of beta cells are destroyed (~80%. Most individuals with type 1 DM have the HLA DR3 and/or DR4 haplotype. Refinements in genotyping of HLA loci have shown that the haplotypes DQA1*0301, DQB1*0302, and DQB1*0201 are most strongly associated with type 1 DM.
Hence, most individuals with type 1 DM do not have a first-degree relative with this disorder.
Pathologically, the pancreatic islets are infiltrated with lymphocytes (in a process termed insulitis). The islet destruction is mediated by T lymphocytes rather than islet autoantibodies.

Islet cell autoantibodies (ICAs) are a composite of several different antibodies directed at pancreatic islet molecules such as GAD glutamic acid decarboxylase (GAD, the biosynthetic enzyme for the neurotransmitter GABA),, insulin, and IA-2/ICA-512 homology with tyrosine phosphatases )and serve as a marker of the autoimmune process of type 1 DM. ICA’s In combination with impaired insulin secretion after IV glucose tolerance testing, they predict a >50% risk of developing type 1 DM within 5 years.
Putative environmental triggers include viruses (coxsackie and rubella most prominently), bovine milk proteins, and nitrosourea compounds. The Diabetes Prevention Trial—type 1 concluded that administering insulin (IV or PO) to individuals at high risk for developing type 1 DM did not prevent type 1 DM.

DM2: The concordance of type 2 DM in identical twins is between 70 and 90%. As insulin resistance and compensatory hyperinsulinemia progress, the pancreatic islets in certain individuals are unable to sustain the hyperinsulinemic state. IGT, characterized by elevations in postprandial glucose, then develops. A further decline in insulin secretion and an increase in hepatic glucose production lead to overt diabetes with fasting hyperglycemia. Ultimately, beta cell failure may ensue. Insulin resistance impairs glucose utilization by insulin-sensitive tissues and increases hepatic glucose output; both effects contribute to the hyperglycemia. Increased hepatic glucose output predominantly accounts for increased FPG levels, whereas decreased peripheral glucose usage results in postprandial hyperglycemia. For example, adipocytes secrete a number of biologic products (nonesterified free fatty acids, retinol-binding protein 4, leptin, TNF-, resistin, and adiponectin). In addition to regulating body weight, appetite, and energy expenditure, adipokines also modulate insulin sensitivity. The increased production of free fatty acids and some adipokines may cause insulin resistance in skeletal muscle and liver
This lipid storage or steatosis in the liver may lead to nonalcoholic fatty liver disease (Chap. 303) and abnormal liver function tests. This is also responsible for the dyslipidemia found in type 2 DM [elevated triglycerides, reduced high-density lipoprotein (HDL), and increased small dense low-density lipoprotein (LDL) particles

Metabolic syndrome: Two distinct syndromes of severe insulin resistance have been described in adults: (1) type A, which affects young women and is characterized by severe hyperinsulinemia, obesity, and features of hyperandrogenism; and (2) type B, which affects middle-aged women and is characterized by severe hyperinsulinemia, features of hyperandrogenism, and autoimmune disorders

demonstrated that intensive changes in lifestyle (diet and exercise for 30 min/day five times/week) in individuals with IGT prevented or delayed the development of type 2 DM by 58% compared to placebo. metformin prevented or delayed diabetes by 31% compared to placebo. acarbose, metformin, thiazolidinediones, and orlistat prevent or delay type 2 DM but are not approved for this purpose. A recent ADA Consensus panel concluded that metformin, but not other medications, could be considered in individuals with both IFG and IGT who are at very high risk for progression to diabetes.

Six different variants of MODY, caused by mutations in genes encoding islet-enriched transcription factors or glucokinase (Fig. 338-4), are transmitted as autosomal dominant disorders. MODY 1, MODY 3, and MODY 5 are caused by mutations in the hepatocyte nuclear transcription factor (HNF) 4, HNF-1, and HNF-1, respectively. Studies of populations with type 2 DM suggest that mutations in MODY-associated genes are rare (<5%) causes of type 2 DM