Diabetes

Three types of diabetes Gestational

Before getting into each type of diabetes we will first discuss normal blood glucose concentration regulation as diabetes of any type results in blood glucose dysregulation

Normal physiological mechanisms of plasma glucose concentration regulation Insulin- blood glucose rises, insulin rises, glucose leaves blood and goes into cells Glucagon-blood glucose falls, glucagon rises, glycogen broken down into glucose and glucose enters blood

Normal physiological mechanisms of plasma glucose concentration regulation Insulin binds to an insulin receptor on liver, skeletal muscle, heart and adipose tissue (major targets) Insulin receptor is a protein with a specific configuration that allows for the binding of insulin Insulin helps glucose get into certain cells so blood glucose levels fall

Normal physiological mechanisms of plasma glucose concentration regulation (hormones involved) https://www.youtube.com/watch?v=eDm9hEOn8zc

How Insulin Decreases Plasma Glucose Level

Carbohydrate Metabolism (Cont’d) Postprandial glucose metabolism in normal individuals: After food is ingested, blood glucose concentrations rise and stimulate insulin release. Insulin action: glucose uptake by the tissues liver glycogen formation and glycogen breakdown lipid synthesis and inhibits fatty acid breakdown to ketone bodies Promotes protein synthesis Insulin stimulates the uptake of amino acids and their conversion to protein In adipose tissue glucose is converted to free fatty acids and stored as triglycerides Liver does not require insulin for glucose transport

Normal physiological mechanisms of plasma glucose concentration regulation (hormone binding) Glucagon binds to an glucagon receptor on liver (major target for glucose release) when blood glucose is low- this causes release of glucose from the liver into the blood Glucagon receptor is a protein with a specific configuration that allows for the binding of glucagon

Causes and consequences of type 1 diabetes including how metabolic syndrome may be part of existing type 1 diabetes Causes- autoimmune attack on beta cells of pancreas-beta cells are destroyed and thus no insulin is produced Autoimmune attack reason is not clear but can be unexplained or due to viruses or food containing nitrogen preservatives cow’s milk given under the age of 6 months (maybe under 1 year of age) has also been a suspect but recent data has ruled that out- still caution should be observed-breast milk is best (formula if no or insufficient breast milk)

Cells destroyed by the body’s immune system

Consequences of type 1 diabetes Microvascular disease Diabetic retinopathy Diabetic nephropathy Diabetic neuropathies Macrovascular disease Cardiovascular disease Stroke Peripheral vascular disease Infection

Type 1 diabetes consequences Diabetes retinopathy Microaneurysm Hemorrhage Exudates Retinal edema Early background retinopathy may reverse with glycemic control

Topics Lecture 1

Type 1 diabetes consequences Diabetes nephropathy 30-40 % of all type 1 DM patients develop nephropathy in 20 years 15-20 % of type 2 DM patients develop nephropathy Manifested as: Microalbuminuria Progressive diabetic nephropathy leading to end-stage renal disease

Type 1 diabetes consequences Diabetes neuropathy Autonomic neuropathy: Manifested by orthostatic hypotension, diabetic diarrhea, erectile dysfunction, and difficulty in urination.

Type 1 diabetes consequences Peripheral vascular disease and foot ulcer Incidence of gangrene of the feet in DM is 20 fold higher than control group due to: - Ischemia - Peripheral neuropathy - Secondary infection

Consequences of type 1 diabetes Macrovascular disease Diabetes mellitus is a major risk factor for coronary artery disease, cerebrovascular disease, and peripheral vascular disease. Multiple risk factors for vascular disease, including obesity, hypertension, hyperglycemia, hyperlipidemia, altered platelet function, and elevated fibrinogen levels, frequently are found in people with diabetes. In type 1 diabetes, the attained age and the duration of diabetes appear to correlate with the degree of macrovascular disease.

What is pre-diabetes-refers to pre-type 2 diabetes? Sometimes pre-diabetes and metabolic syndrome are used interchangeably- both pre-diabetes and metabolic syndrome can lead to type 2 diabetes Pre-diabetes-elevated blood glucose levels but not high enough to be diagnosed as diabetes -same features as metabolic syndrome (elevated waist circumference, hypertension, dyslipidaemia) and their impact mechanisms on glucose dysregulation apply here

Cause of (including metabolic syndrome) of type 2 diabetes Initially, decreased insulin sensitivity due to one or more of genetics, obesity, dyslipidaemia, hypertension, metabolic syndrome (with or without elevated plasma glucose, pre-diabetes (pre-diabetes may also take the form of metabolic syndrome))

Type 2 diabetes- causes Obesity (obesogenic environment) leads to elevated plasma free fatty acids and oxidation which reduces insulin sensitivity (insulin sensitivity is the efficiency with which insulin gets glucose into the cell) Specific free fatty acids are suspect in insulin resistance (e.g. elevated palmitic acid and trans fatty acids, decreased alpha-linolenic acid) (other suspected free fatty acids are under investigation in Barre lab) Dyslipidaemia-can increase insulin resistance via atherosclerosis which increases oxidation which causes insulin resistance Hypertension- can damage arterial endothelium which via atherosclerosis can cause insulin resistance Elevated blood plasma glucose which can cause oxidation which can cause further insulin resistance Genetic susceptibility to impact of obesity or other factors (e.g. diet, lack of physical activity etc) plays a role in insulin resistance

Risk Factors Family History Type 2 DM Obesity Habitual physical inactivity Previously identified impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) Hypertension Hyperlipidemia IFG: > or = 110 and <126 IGT: > or = 140 and <200

Risk of type 2 diabetes algorithm http://canrisk.diabetes.ca/index.php?utm_source=VanityURL&utm_medium=URL&utm_campaign=diabetes.ca/take-the-test ANS: B In DKA, counterregulatory hormones antagonize insulin by increasing glucose production and decreasing tissue use of glucose. Profound insulin deficiency results in decreased glucose uptake, increased fat mobilization with the release of fatty acids, and accelerated gluconeogenesis and ketogenesis. Increased glucagon levels contribute to the activation of glucose-forming and ketone-forming pathways in the liver. Ordinarily, tissues use ketones as an energy source to regenerate bicarbonate. During DKA, bicarbonate buffering does not occur, and the individual develops a metabolic acidosis.

As insulin resistance increases finally get diagnosis of type 2 diabetes

Consequencees of Type 2 Diabetes

Type 2 Diabetes Mellitus Ranges from insulin resistance with relative insulin deficiency to insulin secretory defect with insulin resistance Metabolic syndrome can be part of post-onset type 2 diabetes which can contribute to the worsening of T2D

Type 2 Diabetes Mellitus Consequences As hypertension, dyslipidaemia, elevated blood glucose, elevated free fatty acids, and obesity continue get decreased insulin sensitivity and depressed synthesis and release of insulin Becomes a vicious cycle where beta cells are being progressively asked for more insulin but increased insulin levels are met with increased insulin resistance Finally the beta cells become exhausted and quit due to lipo-/gluco-toxicity Lipotoxicity refers to increased plasma free fatty acid concentrations and their presentation to the alpha-cells in this case Gluco-toxicity refers to increased plasma glucose concentrations and their presentation to the alpha-cells in this case

Heart and blood vessel disease Heart and blood vessel disease. Diabetes dramatically increases the risk of various cardiovascular problems, including coronary artery disease with chest pain (angina), heart attack, stroke, narrowing of arteries (atherosclerosis) and high blood pressure. Nerve damage (neuropathy). Excess sugar can injure the walls of the tiny blood vessels (capillaries) that nourish your nerves, especially in the legs. This can cause tingling, numbness, burning or pain that usually begins at the tips of the toes or fingers and gradually spreads upward. Poorly controlled blood sugar can eventually cause you to lose all sense of feeling in the affected limbs. Damage to the nerves that control digestion can cause problems with nausea, vomiting, diarrhea or constipation. For men, erectile dysfunction may be an issue. Kidney damage (nephropathy). The kidneys contain millions of tiny blood vessel clusters that filter waste from your blood. Diabetes can damage this delicate filtering system. Severe damage can lead to kidney failure or irreversible end-stage kidney disease, which often eventually requires dialysis or a kidney transplant.

Eye damage. Diabetes can damage the blood vessels of the retina (diabetic retinopathy), potentially leading to blindness. Diabetes also increases the risk of other serious vision conditions, such as cataracts and glaucoma. Foot damage. Nerve damage in the feet or poor blood flow to the feet increases the risk of various foot complications. Left untreated, cuts and blisters can become serious infections, which may heal poorly. Severe damage might require toe, foot or leg amputation. Hearing impairment. Hearing problems are more common in people with diabetes.

Skin conditions. T2D may leave one more susceptible to skin problems, including bacterial and fungal infections. Pruritus-itch-yeast infection, dry skin, or poor circulation. When poor circulation is the cause of itching, the itchiest areas may be the lower parts of the legs. Alzheimer's disease. Type 2 diabetes may increase the risk of Alzheimer's disease. The poorer your blood sugar control, the greater the risk appears to be. The exact connection between these two conditions still remains unclear.

Fatigue- glucose catabolism is central to energy production-without sufficient glucose, one becomes tired

Causes and consequences of gestational diabetes

Gestational Diabetes Mellitus (GDM): Gestational Diabetes Mellitus (GDM) develops during some cases of pregnancy but usually disappears after pregnancy.

Gestational Diabetes This diagnosis is given when a woman, who has never had diabetes before, gets diabetes or has high blood sugar, when she is pregnant. Its medical name is gestational diabetes mellitus or GDM. It is one of the most common health problems for pregnant women. The word “gestational” actually refers to “during pregnancy.”

Causes of gestational diabetes Increased insulin resistance - may be due to excessive weight gain especially early in pregnancy -can be due to hormones secreted by the placenta that are “diabetogenic”:

Gestational Diabetes It occurs in about 5% of all pregnancies, which is around 200,000 cases each year. If not treated, gestational diabetes can cause health problems for the mother and the fetus.

Consequences of type 2 diabetes Obstetric complications: Increased incidence of miscarriage Congenital malformations Incidence 4X higher than in general population Most significant remaining cause of fetal death is congenital malformation Association with hypertensive disorders of pregnancy Gestational hypertension Preeclampsia It has long been recognized that poorly controlled diabetes causes a multitude of obstetric complications

Diabetes in Pregnancy: Clinical implications Shoulder dystocia Fetal macrosomia

Complications of gestational diabetes Obstetric complications (cont’d.): Preterm delivery Intrauterine fetal demise Traumatic delivery (e.g., shoulder dystocia) Operative vaginal delivery vacuum-assisted forceps-assisted

Consequences of gestational diabetes Fetal macrosomia Disproportionate amount of adipose tissue concentrated around shoulders and chest Respiratory distress syndrome Neonatal metabolic abnormalities: Hypoglycemia Jaundice Organomegaly Perinatal mortality Long term predisposition to childhood obesity and metabolic syndrome-increased risk of type 2 diabetes in mother and child Other perinatal complications involve both long and short term exposure to high levels of serum glucose.