Normal Glucose Regulation and Diabetes

Learning Outcomes

• Functions of glucose, fat, and proteins include meeting the body's energy needs.
• Insulin's actions impact glucose, fat, and protein metabolism.
• Counter-regulatory hormones are hormones that work against the action of insulin to increase blood glucose levels.
• Type 1 and Type 2 diabetes have distinguishing features that set them apart.
• Metabolic syndrome is associated with the development of Type 2 diabetes.

Normal Glucose Regulation

• In the presence of oxygen, glucose breaks down into carbon dioxide and water.
• Glucose serves as a source of energy for cells and is absorbed into the bloodstream at the intestines.
• Normal cerebral function requires a continuous supply of glucose.
• The body responds to elevated blood sugar by stimulating the pancreas to release insulin.
• Insulin then binds to cell surface membranes, increasing their permeability to glucose.
• After absorption, glucose can be used for energy, stored as glycogen in the liver, or converted into fat.

Carbohydrate Metabolism

• Glycogen and fat can be converted back into glucose when the body needs more energy.
• Excess glucose may be excreted in urine, especially after a high-carbohydrate meal.
• The liver releases glucose into the bloodstream and the pancreas releases a small (basal) amount of insulin in between meals.

Fat Metabolism

• Fat is the most dense form of fuel storage.
• Triglycerides are metabolized into a glycerol molecule and 3 fatty acids (FAs)
• Glycerol molecules can enter the glycolytic pathway used with glucose for energy.
• Fatty acids are stored in tissue and can be used for energy, but can create ketoacidosis.

Protein Metabolism

• Amino acids are the building blocks of proteins.
• The body can only store excessive amino acids in limited amounts.

Glycolysis

• Glycolysis consists of a step-by-step process of breaking down a glucose molecule into pyruvate, NADH, and ATP for energy production.

Glycogenesis

• Glycogenesis is the process of glycogen formation when an excess of glucose is supplied beyond the need for ATP synthesis.
• Glucose is stored in cells up to a saturation point that lasts for about 12-24 hours.
• Glycogen is stored mainly in the liver and muscle.
• Glycogenesis is the reverse process of glycolysis.

Glycogenolysis

• Glycogenolysis refers to the breakdown of stored glycogen to release glucose.
• The process occurs when glucose levels become too low such as in prolonged starvation.
• Glycogenolysis occurs in the liver and muscle tissue in response to hormonal and neural signals.
• Epinephrine, glucagon, and insulin are hormonal signals in glycogenolysis
• Glycogenolysis inhibits glucogenesis.

Gluconeogenesis

• Gluconeogenesis is the synthesis of glucose by the liver from non-carbohydrate sources.
• The process primarily occurs in the liver.
• Amino acids and fats are converted to glucose.
• Stored fat gets converted to fatty acids and/or glycerol.
• Amino acids gets converted to lactic acid.
• Gluconeogenesis can lead to the development of ketones.
• It also plays a role in maintaining acid-base balance.

Functions of the Pancreas

• The exocrine pancreas releases digestive juices through a duct into the duodenum via exocrine acini units.
• The endocrine pancreas (Islets of Langerhans) releases hormones into the blood.
• Beta cells release insulin and amylin.
• Alpha cells release glucagon.
• Delta cells release somatostatin.
• F/PP cells release pancreatic polypeptide.

Insulin

• Insulin is released by beta cells in the Islets of Langerhans in the pancreas.
• It is required by body cells to initiate active transport of glucose into the cell.
• Skeletal cells store glucose as glycogen.
• Adipose tissue stops the release of fatty acids in response to insulin.
• The liver stops gluconeogenesis, starts producing glycogen and fat.
• Insulin stimulates the uptake, use, and storage of glucose.

Glucose-Regulating Hormones

• Amylin slows glucose absorption in the small intestine and suppresses glucagon secretion, which manages postprandial blood sugar.
• Somatostatin decreases GI activity and suppresses glucagon and insulin secretion; it is secreted with a heavy fat/high carb meal.
• Counter-regulatory hormones: -Epinephrine -Cortisol -Growth hormones

Incretins

• Glucagon-like peptides (GLP-1): -Released after a meal -Stimulates insulin secretion -Suppresses glucagon -Delays gatric emptying -Increases satiety
• Growth hormone, cortisol, epinephrine, progesterone, and estrogen are all incretins.
• Estrogen can lead to increased beta cell activity.

Glucose Regulation

• Increased blood glucose results in the release of insulin and amylin from Beta cells.
• Hypoglycemia results in the release of glucagon from Alpha cells.
• Delta cells release Somatostatin.

Glucagon

• Glucagon is secreted by alpha cells in the pancreas.
• It causes the liver to breakdown stored glycogen to produce glucose (Glycogenolysis).
• Glucagon activates gluconeogenesis in the liver.
• It activates lipase, to break down adipose tissue into fatty acids.

Actions of Insulin & Glucagon on Glucose, Fat & Protein Metabolism

• Insulin increases glucose transport into skeletal muscle & adipose tissue and glycogen synthesis, while decreasing gluconeogenesis

• Glucagon promotes glycogen breakdown and increases gluconeogenesis

• Insulin promotes fatty acid (FA) and triglyceride synthesis by the liver. It also increases transport of FA to triglycerides, and maintains fat storage by inhibiting breakdown of stored triglycerides by adipose cell lipase.

• Glucagon activates adipose cell lipase, making more fatty acids available to the body for energy.

• Insulin Increases active transport of amino acids into cells. It also increases protein synthesis while decreasing protein breakdown

• Glucagon increases amino acid uptake by liver cells & conversion to glucose by gluconeogenesis.

Question

• Insulin will be released when blood sugar levels are high.

Review Questions

• Insulin levels are highest after meals
• Insulin levels are lowest when fasting or between meals
• Glucagon levels are highest when blood sugar is low (fasting)

Classifications of Diabetes

• Type 1 Diabetes: -Type 1A: Autoimmune destruction of pancreatic beta cells -Type 1B: Idiopathic diabetes
• Type 2
• Prediabetes
• Gestational
• Drug Induced

Type 2 Diabetes Mellitus

• Accounts for 90-95% of all DM cases with about 80% of cases related to obesity.
• There is a 40% chance of inheriting Type 2 DM if both parents have it.
• Key characteristics of Type 2 DM: -Insulin resistance -Deranged secretion of insulin -Increased glucose production -Beta cells become exhausted, leading to apoptosis.

Risk Factors for Type 2 Diabetes

• Family history
• Obesity
• Ethnicity
• Age
• Gestational diabetes or delivery of babies over 9 lbs
• Hypertension
• Metabolic Syndrome
• Polycystic ovary Syndrome (PCOS)
• Smoking and Alcohol

Type 2 Diabetes

• Initially, increased insulin secretion occurs by the Beta cells to bring down blood sugar (glucose).
• The insulin is not effective and ultimately cannot bring it down.
• The body increases the level of glucose in response to high insulin levels.
• Beta cells eventually become exhausted.

Physical Exam Findings

• Neurologic: some numbness in both feet
• Respiratory: Within Normal Limits (WNL)
• Cardiac: High blood pressure, no edema
• GI: increased thirst and hunger, no changes in weight
• GU: increased urination
• Skin: cellulitis

Diagnostic Criteria for Diabetes

• Fasting blood glucose >126 mg/dL (2 readings).
• A 2-hour plasma glucose during an Oral Glucose Tolerance Test (OGTT) >200 mg/dL.
• Random blood glucose > 200 mg/dL with hyperglycemic symptoms.
• Hemoglobin A1C > 6.5% (2 readings).

Glycated Hemoglobin A1C

• Glycated Hemoglobin A1C is is used to diagnose or monitor diabetes.
• Glucose does not normally go into the RBC, but the membrane is permeable to glucose.
• Glucose will move into the RBC when the glucose level is chronically high.
• Once glucose is in the RBC, it cannot leave.
• The HgbA1C measures the amount of glucose over 120 days.

Hypoglycemia

• Blood glucose level falls below 70 mg/dL.
• Common causes: excessive exercise, alcohol, poor food intake, too much insulin, stress, surgery, and medications.
• The hypothalamus and portal vein in the liver sense a decreased glucose.
• The body responds by sending signals to the adrenal gland, pancreas, and liver.
• Epinephrine and Glucagon get released, causing activation of the SNS which causes most of the signs and symptoms.
• Epinephrine and glucagon promote glycogenolysis and gluconeogenesis in the liver, as hypoglycemia continues.

Hypoglycemia Symptoms

• Mild symptoms (Blood sugar level 100 -55): -Fatigue -Sweating -Hunger -Dizziness -Rapid heart rate -Anxiety -Irritability -Shakiness

• Severe symptoms (Blood sugar level <55): -Blurred vision -Impaired thinking -Confusion -Palpitations -Loss of consciousness -Seizures -Coma

• Treatment: -If a person is awake: Give them juice and something to eat -If the person is not awake: Give IV D50, sublingual glucose

Diabetic Neuropathy

• Somatic neuropathy: -Diminished perception: vibration, pain, temperature -Hypersensitivity: light touch, occasionally severe "burning” pain

• Autonomic neuropathy: -Defects in vasomotor and cardiac responses -Urinary retention -Impaired motility of the gastrointestinal tract -Sexual dysfunction

Hyperosmolar Hyperglycemic Syndrome (HHS)

• Occurs only in patients with Type 2 diabetes.
• HHS is characterized by severe hyperglycemia (>600 mg/dL), hyperosmolality, and dehydration caused by insulin resistance.
• The cells are not absorbing glucose.
• HHS creates the same hyperosmolarity as in DKA, but there is some insulin so there is no ketone formation.

Hyperosmolar Hyperglycemic Syndrome (HHS)

• Can develop over several days to weeks
• Causes: infection, non-compliance with diet or medications, being undiagnosed, substance abuse, alcohol, etc.
• Symptoms: extreme glucose level, rapid/thread pulse, hypotension, profound dehydration, polydipsia, polyuria, confusion, disorientation, possible seizure, or coma
• Treatment: -Hydration (given first) -IV insulin -Electrolyte replacement

Question

• It is necessary to maintain blood glucose no lower than 70 to maintain a continuous supply of glucose for energy.

Why Does Obesity Cause Insulin Resistance

• Increases in adipose and free fatty acids
• Induces inflammation and release of the associated inflammatory mediators
• Increases stress on pancreatic B cells as insulin is increased
• Results in liver increasing glucose in the blood (impaired suppression)

Why Does A Sedentary Lifestyle Increase Insulin Resistance?

• No Exercise

  • Decrease of intracellular enzymes such as pyruvic acid

• Exercise

  • Increases mitochondrial enzymes
  • Increases insulin sensitivity
  • TG get broken into FFA to use for fuel
  • Decrease BS, decrease insulin
  • Increase glucagon
  • Causes uptake of glucose from circulation

Diet and Smoking

• Diet

  • High glycemic carbohydrates lead to several disease processes

• Smoking

  • Induces inflammation
  • Leads to endothelial dysfunction and increases risk of CAD, CVA and peripheral arterial disease