ENDO :DM PART 1: until complications

Metabolic syndrome/Insulin resistance syndrome/Syndrome X

Insulin resistance + HTN + dyslipidemia (dec HDL and inc TG) + central or visceral obesity + T2 DM or IGT/IFG + accelerated cardiovascular disease

choice of insulin use in DKA

Administer intermediate or long-acting insulin as soon as patient is eating. Allow for overlap in insulin infusion and subcutaneous insulin injection

Environment and prevention of type 1 DM

none have been conclusively determined

Severe insulin resistance of T2DM or IGT: 1. type a 2. type b

1. young women, severe hyperinsulinemia, obesity, hyperandrogenism 2. middle-aged women, severe hyperinsulinemia, hyperandrogenism, autoimmune disorders (+) Autoantibodies directed at the Insulin receptor that may block insulin binding or may stimulate the insulin receptor, leading to intermittent hypoglycemia

K correction in DKA

10 meq/h when plasma K < 5.0-5.2 meq/L, ECG normal, urine flow and normal creatinine documented; administer 40-80 meq/h when plasma K < 3.5 meq/L or if bicarbonate is given.

DKA hydration measures

2-3 L of 0.9% saline over first 1-3 h (15-20 ml/kg per hour); subsequently, 0.45% saline at 250-500 mL/h; change to D5 0.45 at 150-250 ml/h when plasma glucose reaches 200 mg/dL (11.2 mmol/L).

Issue 3.1: Who should undergo laboratory testing for diabetes/pre-diabetes?

Laboratory testing for diabetes and pre-diabetes is recommended for individuals with any of the risk factors for Type 2 diabetes mellitus.

Issue 5.2 Who should undergo OGTT as the preferred initial test for screening for diabetes?

A 75-gram OGTT is preferred as the first test in the following individuals who have: 1. A previous FBS showing Impaired Fasting Glucose (100 to 125 mg/dL or 5.6 to 6.9 mmol/L) 2. Previous diagnosis of Cardiovascular Disease (Coronary Artery Disease, Stroke, Peripheral Arteriovascular Disease) or who are at high risk for cardiovascular disease. 3. A diagnosis of Metabolic Syndrome

Issue 2: Should universal screening be done and how should screening be done?

All individuals being seen at any physician's clinic or by any health care provider should be evaluated annually for risk factors for type 2 diabetes and pre-diabetes. Universal screening using laboratory tests is not recommended, as it would identify very few individuals who are at risk.

mechanisms of decreased insulin in type 2 DM

Amyloid deposition: presence of amyloid fibrillar deposits in the islets of with long-standing type 2 DM Chronic hyperglycemia paradoxically impairs islet function ("glucose toxicity") and leads to a worsening of hyperglycemia (improvement in glycemic control improves islet function) increase FFA ("lipotoxicity") and dietary fat may also worsen islet function With long standing DM: dec beta cell mass

Issue 3.2 In what setting/s should testing for diabetes be done?

Because of the need for follow-up and discussion of abnormal results with qualified health care professionals (nurse, diabetes educator, physician), testing should ideally be carried out within the health care setting (clinics, hospitals, local health centers). Testing at any setting should be supervised by a qualified health care professional.

HHS IV insulin

Bolus 0.1 unit/kg, then IV infusion of 0.1unit/kg/hr Once CPG falls to 250-300mg/dl (13.9-16.7mmol/L): shift to dextrose-containing IVF, dec Insulin IV infusion to 0.05-0.1 unit/kg/hr. Continue IV insulin until patient is eating AND can be switched to SC insulin

type 2 dm fat metabolism

Central or visceral obesity: leads to inc circulating free fatty acids (FFA) and adipokines inc FFAS + adipokines = insulin resistance in skeletal muscle and liver dec Production by adipocytes of adiponectin (insulin-sensitizing peptide) hepatic insulin resistance

DKA and HHS

DKA primarily in type 1 but also occurs in individuals who lack immunologic features of type I DM (obese individuals with T2 DM, often of Hispanic or African-American descent) HHS is seen in individuals with type 2 DM

DKA management PEARLS

Decline in plasma glucose within the first 1-2 h may be more rapid and is mostly related to volume expansion Bicarbonate replacement is not usually necessary UNLESS with severe acidosis (pH < 6.9) Phosphate replacement is NOT proven beneficial in DKA

Type I DM pathogenesis

Destruction of pancreatic beta cells Some do NOT have immunologic markers of autoimmune process involving beta cells, thus mechanism is idiopathic and ARE KETOSIS-PRONE (many are are African American or Asian in heritage) Genetically susceptible individuals have normal beta cell mass at birth but begin to lose beta cells over months to years Autoimmune process is triggered by an infectious or environmental stimulus

Issue 1. Classification of Diabetes: How is diabetes classified?

Diabetes mellitus is classified into 4 clinical types according to etiology: Type 1 diabetes mellitus Type 2 diabetes mellitus Gestational diabetes mellitus (GDM) Secondary diabetes

Pathophysiology of Type 2 DM

Early stages: insulin resistance but near-normal glucose tolerance due compensatory inc insulin output by beta cells Progression: insulin resistance and compensatory hyperinsulinemia progress with pancreatic islets in certain individuals unable to sustain the hyperinsulinemic state, development of IGT Overt DM with fasting hyperglycemia: due to further decline in insulin secretion, hepatic glucose production Ultimate event: failure of beta cells

HHS hydration

Fluid replacement must consider that rapidity of reversal or water depletion may worsen neurologic function Give 1-3L NSS over first 2-3h, use 0.45 Nacl if serum Na >150 mmol/L Once hemodynamically stable, use 0.45 NaCl then D5W Correct calculated free water deficit (average 9-10L) over 1-2 days (hypotonic solution at 200-300ml/h)

GESTATIONAL DIABETES MELLITUS (GDM)

Glucose intolerance that is first recognized during pregnancy, regardless of actual time of onset Insulin resistance is related to the metabolic changes of late pregnancy Most revert to normal glucose tolerance post-partum but have a substantial risk (30 to 60%) of developing DM later in life

when is insulin released?

Glucose levels >3.9 mmol/L (>70 mg/dL) *begin with transport into the beta cell by the GLUT2 glucose transporter Glucose phosphorylation by glucokinase is the rate-limiting step that controls glucose-regulated insulin secretion ATP produced during glycolysis inhibits activity of an ATP-sensitive K* channel which induces beta cell membrane depolarization, leading to an influx of calcium and causing insulin secretion

what happens Postprandially

Glucose load elicits a rise in insulin and fall in glucagon, leading to a reversal of these processes Insulin promotes storage of carbohydrate and fat and protein synthesis, with a major portion of post-prandial glucose transported for utilization by skeletal muscle via GLUT4 transporter (insulin-stimulated transport) Brain utilizes glucose in an insulin-independent fashion

key regulator of insulin secretion by the pancreatic beta cell,

Glucose: *others: amino acids, ketopes vai gastrointestinal peptides, and neurotransmitters

other metabolic defects of type 2 DM

Impaired glucose utilization by insulin-sensitive tissues = postprandial hyperglycemia inc Hepatic glucose output = inc FPG Skeletal muscles: greater impairment in glycogen formation than glycolysis accumulation of lipid within skeletal myocytes, impaired fatty acid oxidation and lipid accelerated atherosclerosis

what happens during Low insulin levels:

Inc glucose production by promoting hepatic gluconeogenesis and glycogenolysis, reducing glucose uptake in insulin sensitive tissues (skeletal muscle and fat), thus promoting mobilization of stored precursors such as amino acids and free fatty acids (lipolysis) Glucagon (from pancreatic alpha cells): released when blood glucose or insulin levels are low Stimulates glycogenolysis and gluconeogenesis by the liver and renal medulla

type 2 DM insulin secretion

Initial inc in insulin secretion to maintain normal glucose tolerance progresses to a state of grossly inadequate insulin secretion

most important regulator of Glucose homeostasis

Insulin

HHS pathophysiology

Insulin deficiency + inadequate fluid intake

insulin biosynthesis

Insulin is produced in the beta cells of the pancreatic islets Precursor polypeptide, preproinsulin >> proinsulin (Structurally related to IGF I and II, which bind weakly to the insulin receptor)>> C peptide + A and B chains of insulin, which are connected by disulfide bonds

HHS Laboratory Abnormalities and Diagnosis

Marked hyperglycemia (glucose may be >1000 mg/dL), hyperosmolality (>350 mosmol/L), prerenal azotemia sodium normal or slightly low, corrected serum sodium is usually increased Small anion gap metabolic acidosis may be present secondary to increased lactic acid Moderate ketonuria, if present, is secondary to starvation More pronounced fluid losses and dehydration than in DKA and Higher mortality

prevention of DM

Metformin prevented or delayed diabetes by 31% compared to placebo Metformin considered in individuals with both IFG and IGT who are at very high risk for progression to DM (age < 60 years, BMI 35 kg/m, family history of DM in 19-degree relative, inc TG, dec HDL, HTN, A1C > 6.0%)

PAthophysiology of DM type 1

Pancreatic islets are infiltrated with lymphocytes (insulitis) Post-inflammation: islets become atrophic, most immunologic markers disappear Beta cells susceptible to the toxic effect of TNF-a, IFNg, and IL-1

Issue 3.3 If initial test(s) are negative for diabetes, when should repeat testing bedone?

Repeat testing should ideally be done annually.

Laboratory Abnormalities and Diagnosis of DKA

Serum bicarbonate frequently <10 mmol/L dec Total-body K dec Total-body Na, CI, P, Mg BUT not accurately reflected by serum levels due to dehydration and hyperglycemia inc BUN and Creatinine due to intravascular volume depletion Hyperamylasemia in DKA is usually of salivary origin dec Measured serum Na" due to hyperglycemia (dec by 1.6-mmol/L for each 100 mg/dL rise in the serum glucose) Normal serum sodium in the setting of DKA indicates a more profound water deficit

choice of fluids in DKA

Switch IV fluids to 0.45% saline once hemodynamically stable and with adequate urine output Reduces trend toward hyperchloremia later in the course of DKA (alternate: initial use of LR in place of NSS)

Issue 5.1 What tests and criteria should be used to diagnose diabetes?

The diagnosis of diabetes mellitus can be made based on any of the following criteria 1. Plasma glucose > 126 mg/dl (7.0 mmol/L) after an overnight fast. Fasting is defined as no caloric intake for at least 8 hours up to a maximum of 14 hours. 2. Two-hour plasma glucose > 200 mg/dl (11.1 mmol/L) during an Oral Glucose Tolerance Test (OGTT). The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water after an overnight fast of between 8 and 14 hours. 3. A random plasma glucose > 200 mg/dl (11.1 mmol/L) in a patient with classic symptoms of hyperglycemia (weight loss, polyuria, polyphagia, polydipsia) or with signs and symptoms of hyperglycemic crisis. *Among ASYMPTOMATIC individuals with positive results, any of the three tests should be REPEATED within two weeks for confirmation.

: results from autoimmune beta-cell destruction, leading to absolute insulin deficiency

Type 1 diabetes mellitus (formerly insulin dependent diabetes mellitus or juvenile diabetes mellitus)

results from a progressive insulin secretory defect in the background of insulin resistance

Type 2 diabetes mellitus (formerly non-insulin dependent diabetes mellitus or adult-onset DM):

HYPERGLYCEMIC HYPEROSMOLAR STATE (formerly NONKETOTIC HYPEROSMOLAR STATE)

Typical patient: elderly T2DM patient + several weeks of polyuria, weight loss, dec oral intake At presentation: mental confusion, lethargy, coma Profound dehydration and hyperosmolality NO symptoms of nausea, vomiting, abdominal pain, Kussmaul respirations

Screening based on HPIM

Use FPG or Alc All individuals >45 years every 3 years Earlier age if they are overweight (BMI >25 kg/m) and have one additional risk factor for diabetes Risk factors for Type 2 Diabetes Mellitus

Pancreatic beta cells co-secrete

amylin

MAJOR nonmetabolic complication of DKA therapy:

cerebral edema (seen in children as DKA is resolving)

Type 2 DM and Genetics

concordance in identical twins is between 70 and 90% If with a parent with type 2 DM: inc risk of diabetes If with both parents having type 2 DM: risk in offspring may reach 40%

Insulin resistance in type 2 Dm

decrease in Maximum glucose utilization (30-60% lower than in normal individuals) is "relative" as supranormal levels of circulating insulin will normalize the plasma glucose

Secondary diabetes:

e.g., genetic defects in beta cell function or insulin action, diabetes of the exocrine pancreas (pancreatitis, cystic fibrosis), drug- or chemical-induced diabetes (such as from the treatment of AIDS, after organ transplantation, glucocorticoids), other endocrine diseases (Cushing's syndrome, hyperthyroidism)

Honeymoon phase of type 1 DM

follows the initial clinical presentation of type 1 DM characterized by modest or, rarely, no insulin requirement as endogenous insulin production gradually disappears with continuing autoimmune destruction of the remaining beta cells (after which insulin is completely deficient)

Type 1 Dm Genetics

identical twins 30-70% concordance Major susceptibility gene is in HLA region on chromosome 6 (HLA DR3 and/or DR4 haplotype) Strongest association: DQA1 0301, DQB1 0302 and DQA1 501, DQB1*0201 NOTE: most individuals with these haplotypes do not develop diabetes NOTE: most individuals with type 1 DM do not have a first-degree relative with this disorder (but the risk of developing type 1 DM for relatives of individuals with the disease is considerably higher compared to the risk for the general population)

Type 2 DM characteristics

impaired insulin secretion, insulin resistance, excessive hepatic glucose production, abnormal fat metabolism

lipids and type 2 DM

inc FFA flux from adipocytes leading to + VLDL and TG Synthesis in hepatocytes (hepatic steatosis) May lead to nonalcoholic fatty liver disease and abnormal liver function tests Responsible for dyslipidemia found in type 2 DM (inc TG, HDL, inc small dense LDL particles)

how does ketogenesis occur in DKA

inc lypolysis leads to inc in FFA delivery to liver causing ketosis *ketogenesis is favored by high glucagon

DKA pathophysio

insulin deficiency + inc counterregulatory hormone excess (glucagon, catecholamines, cortisol, GH) Both insulin deficiency and glucagon excess, in particular, are necessary for DKA to develop

marker of the autoimmune process of type 1 DM

islet cell autoantibodies (ICAS): *Present in >75% diagnosed with new-onset type 1 DM, significant minority of individuals with newly diagnosed type 2 DM, occasionally in individuals with GDM (<5%) *Present in 3 to 4% of first-degree relatives of individuals with type 1 DM * Predicts a >50% risk of developing type 1 DM within 5 years

Polycystic ovary syndrome (PCOS):

premenopausal women with chronic anovulation and hyperandrogenism Significant subset has insulin resistance which substantially increases risk for T2 DM (independent of obesity)

DM epidemiology

rapid increase in T2 prevalence due to obesity and dec activity Prevalence increases with the age of the population, similar in men and women but greater in men > 60 years Worldwide estimates project that in 2030 the greatest number of individuals with diabetes will be 45-64 years of age Twofold greater in ethnic groups (African Americans. Hispanic and Native Americans, Pacific Islanders)

lab test accurately reflecting true ketone body level

serum or plasma assays for beta- hydroxybutyrate

INsulin and DKA MGT

short-acting insulin: IV (0.1 units/kg) then 0.1 unit/kg per hour by continuous IV infusion; increase 2- to 3-fold if no response by 2-4 h. If initial serum K is < 3.3 mmol/L (3.3 meg/L), do not administer insulin until the K is corrected. If the initial serum K>5.2mmol/L (5.2 mEq/L), do not supplement K until potassium is corrected

when does DM become evident in Type 1?

until majority of beta cells are destroyed (-80%)