Obesity and Diabetes Flashcards
Blood glucose levels are determined by… (4)
Dietary intake
Tissue uptake
Mobilization
Excretion
What molecules does
1. Liver
2. Adipose
store caloric excess as?
- Glycogen
2. Triglycerides
What are the blood glucose values for
- Post-prandial
- Mean
- Fasting
- ~6.0-8.0 mmol/L
- ~5.5 mmol/L
- ~4.5-6.0 mmol/L
Glucagon
- Target
- Result on target
- Overall effect
- Stimuli
- Hepatocytes (liver)
- Increase glucose release, increase glucose synthesis, increase glycogen breakdown, decrease glucose storage
- Raises blood glucose level (promotes glucose mobilization)
- Low blood glucose (hypoglycemia) - alpha cells secrete it
Insulin
- Targets
- Results on targets
- Overall effect
- Stimuli
- Liver, fat, skeletal muscle
- Increase glucose uptake (all), increase glucose storage (l, f), increase glucose utilization (sm), decrease glycogen breakdown (l), decrease glucose synthesis (l)
- Lowers blood glucose levels (promotes glucose storage and utilization)
- High blood glucose (hyperglycemia) - beta cells secrete it
Insulin protein stucture
Anabolic polypeptide hormone
Secreted exclusively by beta cells of pancreatic islets of Langerhans
Synthesized as a 51 amino acid (proinsulin)
Cleaved by intracellular proteases to generate A and B chain
Linked by 2 disulphide bridges
How does Glucose-Stimulated Insulin Secretion work?
- Glucose enters the pancreatic beta cell via GLUT2 (low affinity transporter, only works when glucose levels are high)
- Glucose is metabolized, elevating intracellular [ATP]
- Elevated [ATP] inhibits ATP-sensitive K+ channel
- Accumulation of K+ inside the cell results in depolarization
- Voltage gated Ca2+ channel is opened, and Ca2+ flows in
- increased intracellular Ca2+ results in exocytic secretion of insulin from storage vesicles into the blood
Diabetes Mellitus
First noticed as causing rapid weight loss and excessive urination
All characterized by high blood glucose
2 primary causes: inadequate insulin secretion, or impairment of insulin action
Type 1 Diabetes
5-10% of all cases Most commonly arises under 20 years old Autoimmune destruction of pancreatic beta cells Reduced or absent insulin secretion Chronic disease
Type 2 Diabetes
90-95% of all cases
Most commonly arises >40 yrs old, but getting younger
Tissue resistance to the biological actions of insulin
Advanced stages associated with insufficient insulin secretion
Chronic disease
Gestational diabetes
5-10% of all pregnancies
Tissue resistance to the biological actions of insulin (mother)
Acute disorder that generally resolves shortly after birth
Pathophysiology of Type 1 Diabetes
Autoimmune destruction of pancreatic beta cells
Cause not well characterized (multifactorial - genetics, environment, pathogen exposure)
Progressive loss of insulin production and GSIS
Loss of tissue glucose uptake and energy storage
Failure to inhibit glucose production and release from the liver
Chronically elevated blood glucose
Acute effects of type 1 diabetes
Excessive urine production Extreme thirst and hunger Rapid heartbeat Nausea, dizziness, confusion Weakness, shaking, fainting
Chronic complications of type 1 diabetes
Extreme weight loss, wasting Damage to blood vessels of eyes and in extremities Kidney damage Peripheral nerve damage Hyperlipidemia Hypertension CV disease
Treatment of Type 1 diabetes
Careful control of diet
Insulin replacement
Even with good management of hyperglycemia, there is an elevated risk of chronic complications
Pathophysiology of type 2 diabetes
Development of insulin resistance in tissues
At early stages, increases insulin secretion can compensate for moderate insulin resistance
But later on elevated insulin secretion cannot compensate for worsening insulin resistance
Reduced glucose uptake and energy storage
Increased liver glucose synthesis and release
Chronic hyperglycemia
Chronic insulin resistance and hyperglycemia is toxic for pancreatic beta cells
What is insulin resistance and what does it result in (5)?
Reduced response of tissues to insulin Results in: Decreased activation of membrane glucose transporters by insulin receptor Decreased glucose uptake Decreased glucose storage Increased glucose synthesis Elevated blood glucose levels
Adipokines
Signalling molecules with hormone-like actions
Synthesized and secreted by adipose tissue
Regulate energy metabolism in adipose as well as other tissues
Ex: leptin, adiponectin, TNFalpha, etc
Acute effects of type 2 diabetes
Same as type 1 Excessive urine production Extreme thirst and hunger Rapid heartbeat Nausea, dizziness, confusion Weakness, shaking, fainting
Chronic complications of type 2 diabetes
Same as Type 1 Extreme weight loss, wasting Damage to blood vessels of eyes and in extremities Kidney damage Peripheral nerve damage Hyperlipidemia Hypertension CV disease
Treatment of Type 2 diabetes
Careful control of diet, exercise, weight loss
Metformin, insulin secretagogues, incretin agents, gliflozins, TZDs, insulin
Even with good management, elevated risk for chronic complications
Therapeutic lifestyle changes for diabetes
Increased physical activity
Diet modification
Weight reduction
6 pharmacological approaches to diabetes
- Insulin and insulin analogues
- Metformin
- Insulin secretagogues
- Incretin agents
- Gliflozins
- Thiazolidinediones
Insulin replacement therapy
Always required for type 1
Not required for all type 2 patients - only when other therapies fail, for severe/advanced cases, used in combo
How is insulin administered?
By subcutaneous injection
It is rapidly degraded by proteolytic enzymes in GI tract so cannot be taken orally
Rate of absorption determines … (3)
Onset of action
Peak activity
Duration of action
3 forms of insulin, and the speed they are absorbed and their duration of action
- Hexamers (slowest at diffusion, slow onset of action, long duration)
- Dimers (in the middle)
- Monomers (fastest at diffusion, rapid onset of action, short duration)
Natural Insulin
- Form
- Onset
- Peak
- Duration
- Hexamers
- 30 min
- 2 hours
- 6-8 hours
Insulin Lispro
- Form
- Onset
- Peak
- Duration
- Single amino acid change - form dimers
- 15 mins
- 30 mins
- 4 hours
Amino acid substitutions affect… (3)
Quaternary structure (hexamers vs dimers) Crystallization properties (high vs low) Solubility (low vs high)
GSIS replacement
Rapid/regular actin insulin
Mimics beta cell release of insulin in response to a nutrient load
Taken just before a meal
Basal replacement
Intermediate/long acting insulin
Administered once or twice daily
Provides constant insulin levels that are relatively stable for many hours
Important to prevent glucose release from liver during fasting state (ex: while sleeping)
3 insulin infusion devices
Good: traditional insulin replacement (monitor levels with glucometer, inject insulin)
Better: insulin infusion pump (monitor levels with glucometer, pump provides 480 small does of rapid acting insulin per day, plus larger bolus at meals)
Best: artificial pancreas (continuous automated monitoring, numerous doses of rapid acting insulin throughout the day)
What is the most common/severe adverse effect associated with insulin replacement therapy?
Hypoglycemia
Can lead to convulsions and coma
Glucose (oral or infusion is the treatment)
Common causes of hypoglycemia
Inadequate carbohydrate consumption
Unusual physical activity
Insulin dose too large
Why is weight gain a common adverse effect of insulin replacement therapy?
Insulin is an anabolic hormone and promotes energy storage
Increased glycogen synthesis in liver and muscle
Increased triglyceride synthesis and storage in adipose tissue
Reduced resting metabolic rate
Metformin
Drug of first choice for type 2 diabetes
Activates AMP-dependent kinase, which is a key regulator of energy metabolism in most cell types
Decreases basal and post-prandial blood glucose
Adverse effects of metformin
GI irritation
Lactic acidosis (reduced liver uptake of lactate for glucose synthesis)
Low risk for hypoglycemia
Insulin secretagogues
Ex: sulfonylureas, meglitinides
Stimulate insulin release from pancreatic beta cells
Inhibit ATP-sensitive K+ channels in pancreatic beta cells (stimulates the GSIS pathway without glucose)
Uncouples insulin release from blood glucose levels
Increased circulating insulin levels can partially/completely compensate for tissue insulin resistance
Adverse effects of insulin secretagogues
Similar to insulin replacement therapy
Hypoglycemia
Weight gain
Incretins
Gastrointestinal derived hormones that regulate pancreatic insulin and glucagon release
Reduced glucagon release and glucose production
Increases insulin release and glucose uptake
Short duration of action - only get action with high glucose levels (not basal insulin secretion)
Incretin agents: DPP-4 inhibitors
Reduce GLP-1 degradation (so increase their levels)
Increases pancreatic GSIS insulin release, and reduced glucagon release
Can partially/fully overcome tissue insulin resistance
Usually used in combo with metformin and/or secretagogues
Adverse effects of DPP-4 inhibitors
GI (nausea, vomiting)
Low risk for hypoglycemia
Pancreatitis (rare)
Incretin agents: Incretin mimetics
Activate pancreatic GLP-1 receptors (agonists)
Increase pancreatic GSIS release, reduce glucagon release
Can partially/fully overcome tissue insulin resistance
Usually used in combo with metformin and/or secretagogues
Requires subcutaneous injection
Adverse effects of Incretin mimetics
GI (nausea, vomiting)
Low risk for hypoglycemia
Pancreatitis (rare)
Thyroid dysfunction/cancer potential risk
Gliflozins
Inhibit renal glucose reabsorption
Used in combo with metformin
Inhibitors of sodium-glucose transporter linked transporter 2 (SGLT2)
Gliflozins block reabsorption and lead to greater urinary glucose excretion
Adverse effects of gliflozins
Hypoglycemia
Urinary tract infections
Dehydration
Thiazolidinediones
Improve insulin sensitivity in many tissues
PPARy agonists
Normalization of adipose tissue function
