WHY REGULATE PLASMA GLUCOSE?

Set Point: 80-100 mg/100 ml plasma

•Glucose is virtually the only fuel the brain can use tomake ATP (also ketones)

•If plasma glucose falls too low, brain activity declines

•If plasma glucose rises too high, there are both acuteand longterm complications – diabetes mellitus

Absorptive state

Post absorptive state

HOW IS ALL THIS REGULATED?

HORMONES!

Hormones that decrease glucose Hormones that increase glucose

Insulin Glucagon

Epinephrine

Growth hormone

Cortisol

How come so many backup systems to prevent low plasma glucose?

Pancreas – insulin staining in brown

EFFECTS OF INSULIN

•Increased numbers of glucose transporters on cell surface

•Activation of enzymes involved in synthesis of glycogen, glycerol,fatty acids, activation of lipoprotein lipase

•Inhibition of enzymes involved in gluconeogenesis, glycogenolysis,conversion of triacylglycerides to fatty acids and glycerol,synthesis of ketones

Net effect = decreased plasma glucose

Absorptive state

Post absorptive state

What causes insulin to be released?

Hormones that decrease glucose Hormones that increase glucose

Insulin Glucagon

Epinephrine

Growth hormone

Cortisol

Effects of glucagon that lead to increased plasma glucose

Liver: • Activation of enzymes that cause gluconeogenesis• Activation of enzymes that promote ketone synthesis• Inhibition of enzymes that cause synthesis of glycogen

What causes glucagon to be released from the pancreas?

Hormones that decrease glucose Hormones that increase glucose

Insulin Glucagon

Epinephrine

Growth hormone

Cortisol

Hormones that decrease glucose Hormones that increase glucose

Insulin Glucagon

Epinephrine

Growth hormone

Cortisol

plasma glucose

Hypothalamus GHRH secretion

Anterior Pituitary

GH secretion

Liver Adipocytes Most cellsGluconeogenesis lipolysis glucose uptake

plasma glucose

fatty acids

Hormones that decrease glucose Hormones that increase glucose

Insulin Glucagon

Epinephrine

Growth hormone

Cortisol

Diabetes Mellitus• Juvenile/insulin dependent/Type I

– often follows viral illness– autoimmune attack on islets– decreased insulin production– Prevalence: 0.2-0.3% of the US population

• adult-onset/non-insulin dependent/Type II)– associated with obesity and older age– insulin levels can be normal or elevated, especially early– peripheral insulin resistance– Prevalence: 6-10% of the US population (and rising)

Genetics of Diabetes Mellitus

• Juvenile/insulin dependent/Type 1– More common in persons of Northern European descent– Sibling relative risk of about 15

• adult-onset/non-insulin dependent/Type 2)– Higher in persons of African, Pacific Island, and Native

American descent– Sibling relative risk of about 3-4– Many whole genome wide studies recently reported

identifying several risk loci

Type 1 diabetes

Acute Complications

• Hyperglycemia– Increased serum glucose leading to loss of water and glucose

in the urine– Hyperosmolarity– Hypotension– Hyperkalemia (increased serum potassium)– Ketosis

• Hypoglycemia– Resulting from overdose of insulin causing excessive uptake

of glucose by cells, manifestations include activation of the sympathetic nervous system

Insulin deficiency

glucose uptakegluconeogenesis

plasma glucose

lipolysis

ketone synthesis

plasma ketones

plasma H+

Brain dysfunction, coma, death

plasma osmolarity

Loss of Na+ andH2O in urine

Blood volume

Blood pressure

Brain blood flow

K+

Na+

K+

Na+

insulinadrenalinaldosterone

K+

K+

acidosisincreased osmolaritycell injury

Hyperkalemia in diabetes mellitus

Consequences of high plasma glucose

• Increased glycosylation of proteins– hemoglobin (useful as an index of average

blood glucose levels over last 3 months)– collagen in basement membrane

Consequences of high plasma glucose

• Distrubances in polyol pathways in cells that do not require insulin for glucose uptake (nerves, lens of the eye, kidney, blood vessels)

Glucose

aldose reductase

sorbitol Increased osmolarity swelling

Impaired ion pumps injury

Chronic Complications

• Atherosclerosis

• Microvascular disease– nephropathy– retinopathy

• Peripheral Neuropathy

• Infections– Leading cause of amputations

Diabetes & Atherosclerosis Potential Mechanisms

• Hypertension• Glycosylation of LDL (decreases liver

uptake)• Decrease in HDL (? via glycosylation)• Glycosylation/protein crosslinking as

cause of vessel injury• Defects in lipoprotein lipase• Enhanced platelet aggregation• Sorbitol accumulation in vessel wall

Diabetic Retinopathy• major cause of blindness

– 10% of type I after 30 yrs– Leading cause of new blindness in the US

• Nonproliferative lesions– BM thickening, edema, hemorrhage

• Proliferative lesions– new blood vessels, fibrous tissue– proliferate over retina over time– secondary to ischemia, microvascular disease– most severe seen in type I

CAUSES OF END STAGE RENAL DISEASE PERCENT OF CASES

Diabetes 34.2Hypertension 29.2Glomerulonephritis 14.2Interstitial nephritis 3.4Cystic kidney disease 3.4Other or unknown 15.4

Diabetic Nephropathy

• approx. 1/3 of type I DM will get renal failure

• Mechanism: basement membrane damage

Peripheral Neuropathy• Mechanisms:

– changes in nerve components (myelin, schwann cells, etc.)

– microvascular disease

• Consequences– pain, abnormal sensation in extremities– touch, pain sensation eventually lost--allows tissue

damage– autonomic nerve dysfunction

• GI tract motility• GU tract dysfunction

Foot ulcer

INFECTIONS

CAUSES OF INFECTIONS

•Decreased neutrophil function - due to high glucose

•More frequent skin eruptions - peripheral neuropathies

•Ischemia - vascular disease

•Increased plasma glucose - good growth medium for microorganisms

TREATMENT

• Juvenile/insulin dependent/Type I– Insulin injections

• adult-onset/non-insulin dependent/Type II)– Diet and exercise– Sulfonylureas (increase insulin release)– Thiazolidinediones (PPAR agonists) – glucophage (metformin) (increases insulin sensitivity)– Insulin (in severe cases when insulin has been depleted)