EPIDEMIOLOGY AND GLOBAL CONSIDERATIONS

fasting state: low insulin levels incr glc production by promoting hepatic gluconeogenesis and glycogenolysis + reduce glc uptake in insulin-sensitive tissues (skeletal muscle and fat), promoting mobilization of stored precursors such as aas and FFAs(lipolysis). Glucagon stimulates glycogenolysis and gluconeogenesis by liver and renal medulla

major portion of postprandial glc used by skeletal muscle, an effect of insulin-stimulated glc uptake (which is why OGTT is about..).
Other tissues, most notably brain, use glucose in an insulin-independent fashion.

Factors secreted by skeletal myocytes (irisin), adipocytes (leptin, resistin, adiponectin, etc.), and bone also influence glc homeostasis.

beta cells; preproinsulin (single-chain 86-aa)--> amino-terminal signal peptide removed--> proinsulin --> cleavage of an internal 31-residue fragment -->C peptide + A (21aa) and B (30aa) chains of insulin connected by disulfide bonds--> stored together and co-secreted from secretory granules;

C peptide cleared more slowly than insulin--> useful marker of insulin secretion + allows discrimination of endo and exo sources of insulin in evaluation of hypoglycemia

islet amyloid polypeptide (IAPP) or amylin co secreted along w/ insulin (major component of amyloid fibrils found in islets of pxs w/ type 2 diabetes)

Incretins: released from neuroendocrine cells of GI tract following food ingestion and amplify glc-stimulated insulin secretion and suppress glucagon secretion.
Glucagon-like peptide 1 (GLP-1), the most potent incretin: released from L cells in small intestine and stimulates insulin secretion only when the blood glc above fasting level.
Incretin analogues or pharmacologic agents that prolong activity of endogenous GLP-1 enhance insulin secretion.

insulin: secreted into portal venous system--> 50% removed and degraded by liver. Unextracted insulin enters systemic circulation

Insulin binding to R--> stimulates intrinsic TyrK activity--> IC signaling molecules (insulin receptor substrates (IRS)) (ex: activation of PI-3-kinase--> stimulates translocation of a facilitative GLUT to cell surface)

Environmental Factors: Identification difficult bc event may precede onset of DM by several years; Putative environmental triggers include viruses (coxsackie, rubella, enteroviruses most prominently), bovine milk proteins, and nitrosourea compounds

most support view that insulin resistance precedes an insulin secretory defect but that diabetes develops only when insulin secretion becomes inadequate;

ethnic groups: different pathophysiology: Latinos have greater insulin resistance + East Asians and South Asians have more beta cell dysfunction; East and South Asians appear to develop type 2 DM at a younger age and a lower BMI. In some groups, DM that is ketosis prone (often obese) or ketosis-resistant (often lean) is seen

Prevention: reduce body weight + incr physical activity + screen for cardiovascular disease. A number of agents, including α-glucosidase inhibitors, metformin, thiazolidinediones, GLP-1 receptor pathway modifiers, and orlistat, prevent or delay type 2 DM but are not approved for this purpose. Individuals with IFG, IGT, or an HbA1c of 5.7–6.4% should be monitored annually to determine if diagnostic criteria for diabetes are present.

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.).

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

most individuals w/ predisposing haplotypes do not develop diabetes.

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.

(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))

significant minority of individuals w/ newly diagnosed type 2

w/ impaired insulin secretion after IV glc tolerance testing--> predict a >50% risk of developing type 1 DM within 5 yrs.

Prevention: None successful

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.

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.

Insulin dose-response curves: rightward shift (reduced sensitivity) + reduced maximal response (overall decr in max glc utilization (30–60% lower than in normal))

is relative bc supranormal levels of circulating insulin will normalize plasma glc.

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

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

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.

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

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

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.

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

(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**

Transient or permanent neonatal diabetes (onset <12 months of age) occurs;
Permanent: several genetic mutations, u. requires treatment with insulin, and phenotypically similar to type 1 DM; Mutations in ATP-sensitive K channel subunits (Kir6.2 and ABCC8) + insulin gene (interfere with proinsulin folding and processing): major causes; may respond to sulfonylureas and can be treated with these agents; mutations often a. w/ a spectrum of neurologic dysfunction

PHYSICAL EXAMINATION

-DM-relevant aspects: weight or BMI, retinal examination, orthostatic BP, foot examination, peripheral pulses, and insulin injection sites.
-BP>140/80 mmHg is considered hypertension in individuals with diabetes.
-periodontal disease more frequent in DM, teeth and gums should also be examined.
-annual foot examination should (1) assess blood flow,
sensation, ankle reflexes, and nail care; (2) look for presence of foot deformities such as hammer or claw toes and Charcot foot; and (3) identify sites of potential ulceration.
-annual screening for distal symmetric neuropathy beginning w/ initial diagnosis + annual screening for autonomic neuropathy 5 yrs after diagnosis of type 1 DM + at time of diagnosis of type 2 DM; includes testing for loss of protective sensation (LOPS) using monofilament testing plus one of the following tests: vibration, pinprick, ankle reflexes, or vibration perception threshold (using a biothesiometer). If monofilament test or one of the other tests is abnormal, the patient is diagnosed with LOPS and counseled accordingly

CLASSIFICATION OF DM IN AN INDIVIDUAL PATIENT

type 1 DM often: (1) onset of disease prior to 30 years; (2) lean body habitus; (3) requirement of insulin as initial therapy; (4) propensity to develop ketoacidosis; and (5) an incr risk of other AI disorders

type 2 DM often: (1) develop after 30 (2) u. obese (80%); (3) may not require insulin therapy initially; and (4) may have associated conditions such as insulin resistance, hypertension, cardiovascular disease, dyslipidemia, or PCOS.; insulin resistance often a. w/ abdominal obesity (as opposed to hip and thigh obesity) and hyperTG.

phenotypic type 2 DM
some present w/ diabetic ketoacidosis but lack AI markers and may be later treated with oral glucose-lowering agents rather than insulin (this clinical picture is sometimes referred to as ketosis-prone type 2 DM).

some (5–10%) do not have absolute insulin deficiency but have AI markers (GAD and other ICA autoantibodies) suggestive of type 1 DM (termed latent AI diabetes of the adult); more likely to be <50 years of age, thinner, and have a personal or family history of other AI disease; more likely to require insulin treatment within 5 yrs.

Monogenic forms of diabetes should be considered in those w/ diabetes onset at <30 years of age, an autosomal pattern of diabetes inheritance, and lack of nearly complete insulin deficiency.

LABORATORY ASSESSMENT

diagnosis + assessing glycemic control

should be screened for DM-associated conditions (e.g., albuminuria, dyslipidemia, thyroid dysfunction).

Serum insulin or C-peptide measurements often do not distinguish type 1 from type 2 DM, but a low C-peptide level confirms a patient’s need for insulin. Many individuals with newonset type 1 DM retain some C-peptide production. Measurement of islet cell antibodies at the time of diabetes onset may be useful if the type of DM is not clear based on the characteristics described above

HISTORY:
-special emphasis on DM-relevant aspects such as weight, family hx of DM and its complications, RFs for cardiovascular disease, exercise, smoking, and ethanol use.
-Symptoms of hyperglycemia: polyuria, polydipsia, weight loss, fatigue, weakness, blurry vision (bc of changes in water content of lens, resolves as hyperglycemia controlled), frequent superficial infections (vaginitis, fungal skin infections), and slow healing of skin lesions after minor trauma.