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