Disorders of Glucose Metabolism Flashcards
What cells in the pancreas are involved in the regulation of blood glucose levels
Beta - release insulin for glucose uptake in cells and the liver to form glycogen
Alpha - release glucagon for glycogen breakdown and glucose release to the bloodstream from the liver
Insulin regime comparison - prandial vs biphasic vs basal
Basal insulin regime provides the best glycemic control over a 3 yr study; with better HbA1c control, fewer hypoglycemic events, and less weight gain.
What is the prognosis of pre diabetes
- 1-5% per yr go on to develop DM
- 50-80% revert to normal glucose tolerance
- weight loss may improve glucose tolerance
- increased risk of developing macrovascular complications (IGT >IFG)
- lifestyle modifications decrease progression to DM by 58%
Pre diabetes diagnostic criteria
- IFG: FPG 6.1-6.9 mmol/L
- IGT: 2h 75 g OGTT 7.8-11.0 mmol/L
- HbA1c: 6.0-6.4%
Diabetes diagnostic criteria
• any one of the following is diagnostic
• FPG ≥7.0 mmol/L (fasting = no caloric intake for at least 8 h)
OR
• 2 h 75 g OGTT ≥11.1 mmol/L
OR
• random PG ≥11.1 mmol/L
OR
• HbA1c ≥6.5% (not for diagnosis of suspected Type 1 DM, children, adolescents, or pregnant women)
- in the presence of hyperglycemia symptoms (polyuria, polydipsia, polyphagia, weight loss, blurry vision), a confirmatory test is not required
- in the absence of hyperglycemic symptoms, a repeat confirmatory test is required to make the diagnosis of diabetes
Pathophysiology of type 1 diabetes
Immune-mediated β cell destruction, usually leading to absolute insulin deficiency
Pathophysiology of type 2 diabetes
Ranges from predominantly insulin resistance with relative insulin deficiency to a predominantly insulin secretory defect with insulin resistance 2º to β cell dysfunction
Outside of type 1 and 2 diabetes mellitus, what are some things that can cause diabetes
a. Genetic defects of β cell function (e.g. MODY – Maturity-Onset Diabetes of the Young) or insulin action
b. Diseases of the exocrine pancreas: Pancreatitis, pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis (“bronze diabetes”)
c. Endocrinopathies: Acromegaly, Cushing’s syndrome, glucagonoma, pheochromocytoma, hyperthyroidism
d. Drug-induced: Glucocorticoids, thyroid hormone, β-adrenergic agonists, thiazides, phenytoin, clozapine
e. Infections: Congenital rubela, CMV, coxsackie
f. Genetic syndromes associated with DM: Down’s syndrome, Klinefelter’s syndrome, Turner’s syndrome
g. Gestational diabetes mellitus
Effect of intensive control in type II diabetes
Intensive blood glucose control reduces microvascular, but not macrovascular complications in type 2 DM
Intensive glycemic control did not reduce all-cause mortality and cardiovascular mortality compared to conventional glycemic control. Intensive glycemic control reduced the risk of microvascular complications while increasing the risk of hypoglycemia. Intensive glycemic control may also reduce the risk of non-fatal MI in trials exclusively deaing with glycemic control in usual care settings
Effect of intensive control in type I diabetes
Intensive treatment of Type 1 DM significantly reduces the development and progression of diabetic retinopathy, nephropathy, and neuropathy in patients with Type 1 DM.
Compare the onset of type 1 vs type 2 diabetes
Type I - Onset Usually <30 yr of age
Type II - Usually >40 yr of age
Increasing incidence in pediatric population 2o to obesit
Compare the epidemiology of type 1 vs type 2 diabetes
1 - More common in Caucasians
Less common in Asians, Hispanics, Aboriginals, and Blacks
Accounts for 5-10% of all DM
2- More common in Blacks, Hispanics, Aboriginals, and Asians
Accounts for >90% of all DM
Compare the etiology of type 1 vs type 2 diabetes
1- Autoimmune
2- Complex and multifactorial
Compare the genetics of type 1 vs type 2 diabetes
1- Monozygotic twin concordance is 30-40%
Associated with HLA class II DR3 and DR4, with either allele present in up to 95% of type 1 DM
Certain DQ alleles also confer a risk
2- Greater heritability than type 1 DM
Monozygotic twin concordance is 70-90%
Polygenic Non-HLA associated
Compare the pathophysiology of type 1 vs type 2 diabetes
1- Synergistic effects of genetic, immune, and environmental factors that cause β cell destruction resulting in impaired insulin secretion
Autoimmune process is believed to be triggered by environmental factors (e.g. viruses, bovine milk protein, urea compounds)
Pancreatic cells are infiltrated with lymphocytes resulting in islet cell destruction
80% of β cell mass is destroyed before features of DM present
2 - Impaired insulin secretion, peripheral insulin resistance (likely due to receptor and post receptor abnormality), and excess hepatic glucose production
Compare the natural history of type 1 vs type 2 diabetes
Type 1- After initial presen ation, honeymoon period often occurs where glycemic control can be achieved with little or no insulin treatment as residual cells are still able to produce insulin Once these cells are destroyed, there is complete insulin deficiency
2- Early on, glucose tolerance remains normal despite insulin resistance as β cells compensate with increased insulin production As insulin resistance and compensatory hyperinsulinism continue, the β cells are unable to maintain the hyperinsulinemic state which results in glucose intolerance and DM
Compare the circulating autoantibodies of type 1 vs type 2 diabetes
1 - Islet cell Ab present in up to 60-85%
Most common islet cell Ab is against glutamic acid decarboxylase (GAD)
Up to 60% have Ab against insulin
2- <10%
Compare the risk factors of type 1 vs type 2 diabetes
1- Personal history of other autoimmune diseases including Graves’, myasthenia gravis, autoimmune thyroid disease celiac disease, and pernicious anemia
Family history of autoimmune diseases
2- Age >40 yr Schizophrenia Abdominal obesity/overweight Fatty liver First-degree relative with DM Hyperuricemia Race/ethnicity (Black, Aboriginal, Hispanic, Asian-American, Pacific Islander) Hx of IGT or IFG HTN Dyslipidemia Medications e.g. 2nd generation antipsychotics PCOS Hx of gestational DM or macrosomic baby (>9 lb or 4 kg)
Compare the body habitus of type 1 vs type 2 diabetes
1- Normal to thin
2- Typically overweight with increased central obesity
Compare the treatment of type 1 vs type 2 diabetes
1- Insulin
2- Lifestyle modification
Non-insulin antihyperglycemic agents - unless contraindicated, metformin should be the initial antihyperglycemic agent of choice.
Additional agents to be selected on the basis of clinically relevant issues, such as glucose lowering effectiveness, risk of hypoglycemia, and effect on body weight
Insulin therapy
Compare the severe complications of type 1 vs type 2 diabetes
1- Diabetic ketoacidosis (DKA) in severe cases
2- Hyperosmolar hyperglycemic state (HHS)
DKA in severe cases
Compare the screening of type 1 vs type 2 diabetes
1- Subclinical prodrome can be detected in first and second-degree relatives of those with type 1 DM by the presence of pancreatic islet autoantibodies
2- Screen individuals with risk factors
Diabetes target guidelines
HbA1c ≤7.0%, HbA1c <6.5%, may be targeted in type 2 DM in patients with a shorter duration of DM with no evidence of significant CVD and longer life expectancy
Fasting plasma glucose 4-7 mmol/L
2h post-prandial glucose 5-10 mmol/L, 5-8 mmol/L if not meeting target A1c and can be safely achieved
Lipids As per high risk group if age >40 or age >30 if DM duration >15 yr
Blood pressure <130/80
Cardiovascular effects of intensive lifestyle intervention in T2DM
An intensive lifestyle intervention focusing on weight loss did not significantly reduce the rate of cardiovascular events in overweight or obese adults with type 2 DM.
When should non insulin antihyperglycemic agents be added in T2DM
- initiate non-insulin antihyperglycemic therapy within 2-3 mo if lifestyle management does not result in glycemic control
- if initial HbA1c >8.5% at the time of diagnosis, initiate pharmacologic therapy with metformin immediately and consider combination of therapies or insulin immediately
- continue to add additional pharmacologic therapy in a timely fashion to achieve target HbA1C within 3-6 mo of diagnosis
DDP 4 inhibitors mechanism of action
- Antihyperglycemic agents (e.g. sitagliptin, saxagliptin, linagliptin) that inhibit DPP-IV, which is an enzyme that degrades endogenous incretin hormones like GLP-1
- Incretin hormones stimulate glucose dependent insulin secretion and inhibit glucagon release from the pancreas
GLP 1 analogues mechanism of action
- Human glucagon-like peptide-1 analogues: exenatide, liraglutide
- These activate GLP-1 causing increased insulin secretion, decreased inappropriate glucagon secretion, increased β-cell growth/replication, slowed gastric emptying, and decreased food intake
- Associated with weight loss
- Subcutaneous formulation
Estimated total daily insulin requirement calculation
0.5-0.7 units/kg (often start with 0.3-0.5 units/kg/d
Intensive glucose lowering therapy HBA1C <6% in type 2 DM outcomes
Intensive glucose lowering therapy in type 2 DM does not improve clinic outcomes and actually increases the risk of mortality with more adverse events compared to standard therapy. Additional research is required to discern the cause.
Effects of intensive BP control in T2DM
Intensive BP lowering to less than 120 mmHg vs. 140 mmHg in patients with type 2 DM and CV risk factors does not reduce major CV event risk reduction except for stroke events
Bolus insulins, onset, peak and duration of action
Rapid acting - 10 min onset, 1-1.5 h peak, 3-5 h duration Novorapid (aspart) Fiasp (faster aspart) Humalog (lispro) Apidra (glulisine)
Short acting - 30 min onset, 2-3 hour peak, 6.5 h duration
Humulin R
Novolin Toronto
Basal insulins, onset, peak, duration
Intermediate acting - 1-3h onset, 5-8 h peak, up to 18h duration
Humulin N
Novolin NPH
Long acting basal insulin analogues - onset 90 min, no peak, up to 24h
Levemir (detemir)
Lantus/Basaglar (glargine 100 units/mL)
Toujeo (glargine 300 units/ml)
Pre mixed insulins
Pre mixed Regular insulin - NPH
Humulin 30/70
Novolin 30/70
Premixed insulin analogues
Biphasic insulin aspart (Novomix 30)
Insulin lispro/lispro protamine (Humalog Mix25 and Mix50)
Effects of combination lipid therapy in T2DM
The addition of fibrate therapy to statin therapy in patients with type 2 DM does not reduce major CV event risk
Treatment of DKA/HHS
- Fluids
- Insulin
- Potassium
- Search for and treat precipitant
Starting insulin regimen for T2DM
Non-insulin antihyperglycemic agent + basal insulin
Start with 10 units of basal insulin at bedtime
Titrate up by 1 unit until FPG <7.0 mmol/L
Starting insulin regimen for T1DM
Basal-bolus (multiple daily injections MDI):
Estimated total insulin requirement is 0.5-0.7 U/kg
40% is given as basal insulin at bedtime
20% is given as bolus insulin before breakfast, lunch, and dinner
Continue metformin but discontinue secretagogue
Premixed:
Estimated total insulin requirement is 0.5-0.7 U/kg
2/3 dose is given as pre-mixed insulin before breakfast 1/3 dose is given as pre-mixed insulin before dinner
Continue metformin but discontinue secretagogue
How should you titrate insulin dose with a high am sugar
Increase bedtime basal insulin
How should you titrate insulin dose with a high lunch sugar
Increase AM rapid/regular insulin
How should you titrate insulin dose with a High supper sugar
Increase lunch rapid/regular insulin, or Increase AM basal insulin
How should you titrate insulin dose with a High bedtime sugar
Increase supper rapid/regular insulin
How to calculate a patient’s supplemental/correction scale
Correction Factor (CF) = 100/Total Daily Dose of insulin (TDD)
■ BG <4: call MD and give 15 g carbohydrates
■ BG between 4 to 8: no additional insulin
■ BG between 8 to (8 + CF): give one additional unit
■ BG between (8 + CF) to (8 + 2CF): give two additional units
■ BG between (8 + 2CF) to (8 + 3CF): give three additional units
Factors that can precipitate DKA
Infection Ischemia or Infarction Iatrogenic (glucocorticoids) Intoxication Insulin missed Initial presentation Intra-abdominal process (e.g. pancreatitis, cholecystitis) Intraoperative/perioperative stress
What insulin is delivered through insulin pump
external battery-operated device provides continuous basal dose of rapid-acting insulin analogue (aspart, glulisine or lispro) through small subcutaneous catheter
• at meals, patient programs pump to deliver insulin bolus
DKA pathophysiology
- Usually occurs in type 1 DM
- Insulin deficiency with inc coun erregulatory hormones (glucagon, cortisol, catecholamines, GH)
- Can occur with lack of insulin (non-adherence, inadequate dosage, 1st presentation) or increased stress (surgery, infection, exercise)
- Unopposed hepatic glucose production -> hyperglycemia -> osmotic diuresis -> dehydration and electrolyte disturbance -> dec Na+ (water shift to ECF causing pseudohyponatremia)
- Fat mobilization -> inc FFAg ketoacids -> metabolic acidosis
- Severe hyperglycemia exceeds the renal threshold for glucose and ketone reabsorption -> glucosuria and ketonuria
Total body K+ depletion but serum K+ may be normal or elevated, 2º to shift from ICF to ECF due to lack of insulin, inc plasma osmolality
• Total body PO43- depletion
DKA clinical features
- Polyuria, polydipsia, polyphagia with marked fatigue, N/V
- Dehydration (orthostatic changes)
- LOC may be decreased with ketoacidosis or with high serum osmolality (osm >330 mmol/L)
- Abdominal pain
- Fruity smelling breath
- Kussmaul’s respiration
DKA serum labs
- Inc BG (typically 11-55 mmol/L, dec Na+ (2º to hyperglycemia -> for every inc in BG by 10 mmol/L) there is a dec in Na+ by 3 mmol/L)
- Normal or inc K+, dec HCO3–, inc BUN, inc Cr, ketonemia, dec PO43
- inc osmolality
DKA ABG
- Metabolic acidosis with inc AG, possible 2º respiratory alkalosis
- If severe vomiting/dehydration there may be a metabolic alkalosis
DKA urine
• +ve for glucose and ketones
DKA treatment
- ABCs are first priority
- Monitor degree of ketoacidosis with AG, not BG or serum ketone level
• Rehydration
– 1 L/h NS in first 2 h
– after 1st 2 L, 300-400 mL/h NS. Switch to 0.45% NaCl once euvolemic (continue NS if corrected sodium is falling faster than 3 mosm/kg water/h)
– once BG reaches 13.9 mmol/L then switch to D5W to maintain BG in the range of 12-14 mmol/L
• Insulin therapy
– critical to resolve acidosis, not hyperglycemia
– do not use with hypokalemia (see below), until serum K+ is corrected to >3.3 mmol/L
– use only regular insulin (R)
– maintain on 0.1 U/kg/h insulin R infusion
– check serum glucose hourly
• K+ replacement
– with insulin administration, hypokalemia may develop
– if serum K+<3.3 mmol/L, hold insulin and give 40 mEq/L K+ replacement
– when K+ 3.5-5.0 mmol/L add KCL 20-40 mEq/L IV fluid to keep K+ in the range of 3.5-5 mEq/L
• HCO3–
– if pH <7.0 or if hypotension, arrhythmia, or coma is present with a pH of <71 give HCO3– in 0.45% NaCl
– do not give if pH >7.1 (risk of metabolic alkalosis)
– can give in case of life-threatening hyperkalemia
• ± mannitol (for cerebral edema)
DKA prognosis
- 2-5% mortality in developed countries
- Serious morbidity from sepsis, hypokalemia, respiratory complications, thromboembolic complications, and cerebral edema (the latter in children)
Hyerosmolar hyperglycemic state (HHS) pathophysiology
Occurs in type 2 DM
- Often precipita ed by sepsis, stroke, MI, CHF, renal failure, trauma, drugs (glucocorticoids, immunosuppressants, phenytoin, diuretics), dialysis, recent surgery, burns
- Partial or relative insulin deficiency decreases glucose utilization in muscle, fat, and liver while inducing hyperglu-cagonemia and hepatic glucose production
Presence of a small amount of insulin prevents the development of ketosis by inhibiting lipolysis
- Characterized by hyperglycemia, hyperosmolality and dehydration without ketosis
- More severe dehydration compared to DKA due to more gradual onset and inc duration of metabolic decompensation plus impaired fluid intake which is common in bedridden or elderly
- Volume contraction -> renal insufficiency -> inc hyperglycemia, inc osmolality -> shift of fluid from neurons to ECF -> mental obtundation and coma
Hyerosmolar hyperglycemic state (HHS) clinical features
- Onset is insidious -> preceded by weakness, polyuria, polydipsia
- History of decreased fluid intake
- History of ingesting large amounts of glucose containing fluids
- Dehydration (orthostatic changes)
- dec LOC -> lethargy, confusion, comatose due to high serum osmolality
- Kussmaul’s respiration is absent unless the underlying precipitant has also caused a metabolic acidosis
Hyerosmolar hyperglycemic state (HHS) serum values
• inc BG (typically 44.4-133.2 mmol/L)
• In mild dehydration, may have hyponatremia (spurious 2º to hyperglycemia -> for every inc in BG by 10 mmol/L there is a dec in Na+ by 3 mmol/L)
– if dehydration progresses, may get hypernatremia
- Ketosis usually absent or mild if starvation occurs
- inc osmolality
Hyerosmolar hyperglycemic state (HHS) ABG
• Metabolic acidosis absent unless underlying precipitant leads to acidosis (e.g. lactic acidosis in MI)
Hyerosmolar hyperglycemic state (HHS) urine
-ve for ketones unless there is starvation ketosis
• Glycosuria
Hyerosmolar hyperglycemic state (HHS) treatment
• Same resuscitation and emergency measures as DKA
• Rehydration
– IV fluids: 1 L/h NS initially
– evaluate corrected serum Na+
– if corrected serum Na+ high or normal, switch to 0.45% NaCl (4-14 mL/ kg/h)
– if corrected serum Na+ low, maintain NS (4-14 mL/kg/h)
– when serum BG reaches 13.9 mmol/L switch to D5W
• K+ replacement
– less severe K+ depletion compared to DKA
– if serum K+<3.3 mmol/L, hold insulin and give 40 mEq/L K+ replacement
– if K+ is 3.3-5.0, give KCl 20-30 mEq/L IV fluid
– if serum K+ ≥5.5 mmol/L, check K+ every 2 h
• Search for precipitating event
• Insulin therapy
– use only regular insulin (R)
– initially load 0.1 U/kg body weight insulin R bolus
– maintenance 0.1 U/kg/h insulin R infusion or IM
– check serum glucose hourly
– in general lower insulin requirement compared to DKA
Hyerosmolar hyperglycemic state (HHS) prognosis
• Overall mortality approaches 50% primarily because of the older patient population and underlying etiology/precipitant
Macrovascular complications associated with diabetes
increased risk of CAD, ischemic stroke, and peripheral arterial disease secondary to accelerated atherosclerosis
Leading cause of death in type 2 DM
CAD
Average fluid losses in DKA and HHS
Average fluid loss runs at 3-6 L in DKA, and 8-10 L in HHS
Management of diabetes to prevent macrovascular complications
■ tight blood pressure control (<130/80 mmHg); especially for stroke prevention
■ tight glycemic control in early DM without established CVD
■ tight low density lipoprotein (LDL) cholesterol control (LDL ≤2.0 mmol/L)
■ ACEI or angiotensin receptor blocker in high-risk patients
■ smoking cessation
■ for adults with CVD who do not meet glycemic targets, recommended to add anti-hyperglycemic agent with demonstrated cardiovascular benefit (empagliflozin or liraglutide) to reduce the risk of major cardiovascular events
Things to consider in a patient with negative serum or urinary ketones with a clinical picture of DKA or increasing serum or urinary ketones as DKA is treated
The nitroprusside test for ketones identifies acetone and acetoacetate but does NOT detect β-hydroxybutyrate (BHB), the ketone most frequently in excess. This has two clinical consequences:
- Be wary of a patient with a clinical picture of DKA but negative serum or urinary ketones. These could be false negatives because of the presence of BHB
- As DKA is treated, BHB is converted to a etone and acetoacetate. Serum or urinary ketones may therefore rise, falsely suggesting that the patient is worsening when in fact they are improving
Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes
Adding Empagliflozin to standard treatment for Type 2 DM reduced death from macrovascular complications and all-cause mortality when compared to placebo
Diabetic retinopathy epidemiology
- type 1 DM: 25% affected at 5 yr, 100% at 20 yr
- type 2 DM: 25% affected at diagnosis, 60% at 20 yr
- leading cause of blindness in North America between he ages of 20-74
- most important factor is disease duration
