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Diabetes mellitus: Diagnosis, Classification, and Pathophysiology…

- - - - other islet cell types (alpha, delta [somatostatin], or PP [pancreatic polypeptide]) similar to beta but spared from AI destruction.
      - insulitis: islets have a modest infiltration of lymphocytes--> beta cells destroyed--> infl process abates + islets become atrophic.
      - abnormalities in humoral + cellular
        
        (1) islet cell autoAbs: do not react w/ cell surface of islet cells + not capable of transferring DM to animals (don't mediate islet destruction)
        
        (2) activated lymphocytes in islets, peripancreatic lymph nodes, and systemic circulation;
        
        (3) T lymphocytes that prolif when stimulated w/ islet prs: islet destruction mediated by T lymphocytes
        
        (4) release of cytokines within insulitis: Beta particularly susceptible to toxic effect of some cytokines (TNF-α, IFNγ, IL-1).
      - mechanisms of beta death may involve formation of NO metabolites, apoptosis, and direct CD8+ T cell cytotoxicity
      - Efforts to suppress AI process at time of diagnosis of diabetes: largely ineffective or only temporarily effective in slowing beta cell destruction.
      - beta of type 1 DM do not differ from beta of normal individuals because islets transplanted from a genetically identical twin are destroyed by a recurrence of AI process of type 1 DM.
    - - a composite of several different abs directed at pancreatic islet molecules (GAD, insulin, IA-2/ICA-512, and ZnT-8)
      - a marker of AI process of type 1 DM (useful in classifying type of DM as type 1 + identifying nondiabetic individuals at risk( (research tool since no treatment prevents progression))
      - present in
        
        majority (>85%) diagnosed w/ new-onset type 1 DM
        
        significant minority of individuals w/ newly diagnosed type 2
        
        occasionally GDM (<5%).
        
        3–4% of first-degree relatives of individuals w/ type 1 DM
      - w/ impaired insulin secretion after IV glc tolerance testing--> predict a >50% risk of developing type 1 DM within 5 yrs.
    - - concordance in identical twins: 40-60%
      - Susceptibility genes
        
        major gene: HLA region on chromosome 6 (MHC II which present Ag Th cells);
        
        Most have HLA DR3 and/or DR4 haplotype
        
        haplotypes DQA10301, DQB10302, and DQB1*0201 most strongly a. w/ type 1 DM.
        
        other genomic associations: (polymorphisms in the promoter region of the insulin gene, the CTLA-4 gene, interleukin 2 receptor, CTLA4, and PTPN22, etc.).
        
        most individuals w/ predisposing haplotypes do not develop diabetes.
      - protection genes
        
        haplotype DQA10102, DQB10602
      - risk of developing type 1 DM incr 10x in relatives, risk is relatively low: 3–4% if the parent has type 1 DM and 5–15% in a sibling--> most individuals w/ type 1 DM do not have a first-degree relative with this disorder
  - - - concordance in identical twins: 70-90%
      - Individuals w/ a parent w/ type 2: incr risk of diabetes; if both parents: risk 40%. Insulin resistance present in many nondiabetic, first-degree relatives of individuals w/ type 2.
      - polygenic + multifactorial; in utero environment also contributes, and either incr/decr birth weight incr risk of type 2 DM in adult life.
      - predisposing genes: large number that convey a relatively small risk;
        
        Most prominent: a variant of TF 7–like 2 gene
        
        Genetic polymorphisms found in genes encoding peroxisome proliferator– activated receptor γ, inward rectifying potassium channel, zinc transporter, IRS, and calpain 10.
    - - charac by impaired insulin secretion + insulin resistance (relative contribution of each varies from individual to individual), excessive hepatic glc production, and abnormal fat metabolism.
      - FIGURE 417-7
    - - Abnormal Muscle and Fat Metabolism
        
        Insulin resistance
        
        is relative bc supranormal levels of circulating insulin will normalize plasma glc.
        
        results from genetic susceptibility + obesity
        
        results in hyperglycemia by
        
        impairing glc utilization by insulin-sensitive tissues: accounts for postprandial hyperglycemia/IGT; in skeletal muscle: a greater impairment in nonoxidative glc usage (glycogen formation) than in oxidative glc metabolism through glycolysis; Glc metabolism in insulin-independent tissues not altered in type 2 DM.
        
        incr hepatic glc output: accounts for incr FPG levels/ IFG
        
        molecular mechanism: “postreceptor” defects in insulin-regulated phosphorylation/dephosphorylation: predominant role in insulin resistance (not decr R levels, those are probably as a result of hyperinsulinemia)
        
        impaired FA oxidation + accumulation of lipid within skeletal myocytes--> impair mitC oxidative phosphorylation + reduce insulin-stimulated mitC ATP production + generate ROS
        
        not all insulin signal transduction pathways are resistant to effects of insulin (those controlling cell growth and diff using mitogenic-activated pr kinase pathway)--> hyperinsulinemia may incr insulin action through these--> accelerating diabetes related conditions such as atherosclerosis
        
        Insulin dose-response curves: rightward shift (reduced sensitivity) + reduced maximal response (overall decr in max glc utilization (30–60% lower than in normal))
        
        Obesity: incr adipocyte mass-->
        
        incr
        
        circulating FFAs--> impair glc utilization in skeletal muscle, promote glc production by liver, and impair beta cell function
        
        adipocyte products + some adipokines--> infl state (infl markers IL-6 and C-reactive pr often elevated); infl cells found infiltrating adipose tissue; Inhibition of infl signaling pathways (ex NF-κB pathway) decr insulin resistance
        
        decr adiponectin production, an insulin-sensitizing peptide--> hepatic insulin resistance.
      - Impaired Insulin Secretion
        
        metabolic environment may also negatively impact islet function:
        
        chronic hyperglycemia paradoxically impairs islet function (“glucose toxicity”) --> worsening of hyperglycemia; Improvement in glycemic control often a. w/ improved islet function
        
        elevation of FFAs (“lipotoxicity”) and dietary fat--> worsen islet function
        
        Reduced GLP-1 action--> reduced insulin secretion
        
        Initially, insulin secretory defect mild + selectively involves glc-stimulated insulin secretion, including a greatly reduced first secretory phase; response to other nonglc secretagogues (ex arginine) preserved, but overall beta function reduced by 50% at onset of type 2 DM; Beta cell mass decr by 50% in individuals w/ longstanding type 2
        
        insulin secretory defect progressive: reason: maybe a second genetic defect— superimposed upon insulin resistance—leads to beta cell failure.
        
        Abnormalities in proinsulin processing--> incr secretion of proinsulin
        
        Islet amyloid polypeptide or amylin, co-secreted by beta cell, forms amyloid fibrillar deposit found in islets of individuals w/ long-standing type 2
      - Increased Hepatic Glucose and Lipid Production
        
        Incr hepatic glc production occurs early in course of diabetes, although likely after onset of insulin secretory abnormalities and insulin resistance in skeletal muscle.
        
        insulin resistance in adipose--> lipolysis + FFA flux incr--> incr lipid (VLDL + TG) synth in hepatocytes--> lipid storage or steatosis in liver--> nonalcoholic fatty liver disease + abnormal liver function tests + dyslipidemia found in type 2 DM (elevated TG, reduced HDL, incr LDL particles)
    - - The metabolic syndrome, the insulin resistance syndrome, and syndrome X: a constellation of metabolic derangements that includes insulin resistance, HTN, dyslipidemia, central or visceral obesity, type 2 DM or IGT/IFG, and accelerated cardiovascular disease.
      - A number of relatively rare forms of severe insulin resistance
        include features of type 2 DM or IGT; Mutations in insulin R that interfere with binding or signal transduction are a rare cause of insulin resistance; Acanthosis nigricans + signs of hyperandrogenism (hirsutism, acne, and oligomenorrhea in women): common physical features.
      - Two distinct syndromes of severe insulin resistance have been described in adults:
        
        (1) type A: affects young women + charac by severe hyperinsulinemia, obesity, and features of hyperandrogenism; undefined defect in insulin-signaling pathway;
        
        (2) type B: affects middle-aged women + charac by severe hyperinsulinemia, features of hyperandrogenism, and AI disorders; autoAbs against insulin R--> block/stimulate--> intermittent hypoglycemia**
      - PCOS: a common disorder that affects premenopausal women + charac by chronic anovulation and hyperandrogenism; Insulin resistance is seen in a significant subset of women with PCOS, and the disorder substantially incr risk for type 2 DM, independent of the effects of obesity