Lecture 8: Diabetes And Hypoglycemia Flashcards by Jhaunte Braithwaite

What is diabetes mellitus?

Includes a heterogenous group of disorders characterized by the presence of hyperglycemia (high blood glucose levels) due to defective secretion of insulin OR action of insulin OR both
Diabetes affects many organs – can result in blindness, renal failure, cardiovascular disease, stroke ……
There is a worldwide increase in the incidence of Diabetes mellitus (concomitant with the incidence of obesity) - ‘DIABESITY’

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What is type 1 diabetes mellitus?

Autoimmune destruction of pancreatic β-cells, progressive destruction and marked reduction in insulin secretion
Insulin levels: Very low or absent; Very low C-peptide
10% of patients with diabetes mellitus
Age of onset: Adolescence (young adults)
Abrupt onset when loss of 80-90% of beta-cells
Ketoacidosis common complication
Life-long insulin therapy to prevent complications (Ketosis)

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What are the risk factors for type 2 diabetes mellitus?

• Risk factors:
• Abdominal obesity (Syndrome X/ Metabolic syndrome/ insulin resistance
syndrome/ central obesity) • Sedentary lifestyle
• And aging

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Whaat happens in type 2 diabetes?

Target tissues (liver, skeletal muscle & adipose tissue) do not respond to circulating insulin (insulin resistance) and decrease in insulin secretion (decreased insulin secretion)
Oral hypoglycemic agents and insulin may be required in later stages
Ketoacidosis – not as common as in type 1
Obesity in children - type 2 diabetes in children. Insulin resistance rather than insulin deficiency. Major public health concern

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What is the significance of insulin resistance in diabetes?

Less-than-expected (suboptimal) biological effect of insulin
200 U of insulin/day for glycemic control
Anthropometric risk factors
BMI > 30 (obesity)
Higher waist circumference (Central obesity)
Waist to hip ratio (WHR) greater than 1 (Abdominal obesity)
In central obesity, (most common cause of insulin resistance)
Decreased number of insulin receptors • And a post-receptor failure

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How is adipocytes an endocrine organ?

• Storage organ for triacylglycerols
• Weight gain (central obesity) results in
Decreased Adiponectin
• Increased secretion of leptin
• Reduced secretion of adiponectin
• Secretion of pro-inflammatory cytokines
• Contribute to insulin resistance

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Explain the impact of adipocytes as an endocrine

Increased leptin

appetite & energy balance
reproduction
insulin sensitivity
immunity

Decreased Adiponectin
-insulin sensitivity

Pro-inflammatory cytokines
-insulin sensitivity

Angiotensinogen
-blood pressure

PAI-1
-haemostasis

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Describe the mechanism of insulin resistance

Insulin resistance in central obesity
– Reduced adiponectin levels: Impairs fat metabolism
– Elevated leptin (leptin resistance) impairs insulin action
– Elevated free fatty acids from visceral adipose tissue • Impairs action of insulin on liver
• Reduce glucose utilization and cause hyperglycemia
• Impairs insulin secretion from pancreas
– Low glucagon like peptide-1 (GLP-1):
Incretin stimulates insulin secretion. Incretins released
from intestinal endocrine cells
(refer pg 310; c. Gastrointestinal hormones)
– Pro-inflammatory cytokines (IL-6, TNF-alpha)

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Describe the progression of type 2 diabetes mellitus

Initial stages, hypersecretion of insulin (insulin resistance), target tissues not responsive to insulin (fewer insulin receptors/ post-receptor defect). Later stages, decreased (suboptimal) insulin secretion from β-cells (β-cell
dysfunction) with insulin resistance

Obese individuals develop insulin resistance, which may precede the development of diabetes by 10 or more years
Patients diagnosed with type 2 diabetes initially show insulin resistance with compensatory hyperinsulinemia
Subsequently, B-cell dysfunction occurs, marked by declining insulin secretion and worsening hyperglycemia

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What are the presenting features of diabetes mellitus ?

Classical triad: Polyphagia, Polydipsia, & Polyuria - more common in type 1
Weight loss (type 1) – Accelerated lipolysis and muscle proteolysis
Ketoacidosis more common in type 1
Insulin deficiency leads to increased muscle proteolysis and negative nitrogen balance. (Remember, insulin facilitates entry of amino acids into muscle and increases protein synthesis)
Insulin deficiency results in adipose tissue lipolysis (Remember, insulin favors storage of TAG)
Decreased secretion of insulin due to beta-cell destruction→ Hyperglycemia
Diabetes mellitus affects carbohydrate, lipid and protein metabolism

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What are the presenting features of type 2 diabetes mellitus?

Many type 2 diabetics are obese (insulin resistance)
Insidious/ asymptomatic onset – detected by screening tests • Hyperglycemia present for many years before symptoms
Typical symptoms: frequent changes in vision (prescription glasses); repeated infections; polyuria and polydipsia

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Summarize mechanism of hyperglycemia in type 1 and type 2 diabetes mellitus

Decreased number of insulin receptors/ post receptor defects (insulin resistance)

Increased glucose production by liver

Decreased number of GLUT-4 in peripheral tissues

Decreased secretion of insulin from the pancreas

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Explain the dyslipidemia in insulin resistance and type 2 diabetes mellitus

• Lipoprotein abnormalities commonly observed are
• Increased small dense LDL (LDL-B) - atherogenic
• Decreased HDL levels
• Increased serum triacylglycerol (Increased VLDL) – reduced activity of lipoprotein
lipase – Remember, lipoprotein lipase requires insulin for optimum activity
• Atherogenic lipid profile →atherosclerosis (macrovascular) - Cardiovascular disease
• Increased circulating free fatty acids due to increased breakdown of TAGs in adipose tissue – contributes to insulin resistance and reduced insulin secretion
• Markers indicating insulin resistance • Elevated serum free fatty acids
• Increased serum TAG: HDL ratio

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What are the laboratory tests for diagnosis and long-term management of diabetes mellitus?

Fasting plasma glucose > 126 mg/dL: Screening test – 8 hours after meal • Random plasma glucose (>200mg/dL) with one of symptoms
Elevated HbA1c levels >6.5%
Oral glucose tolerance test (OGTT)
Evaluates the ability to regulate glucose metabolism
Considered as the ‘gold standard test’
Used to identify patients with ‘prediabetes’ and gestational diabetes • 2-hour plasma glucose >200mg/dL after 75 gms of glucose (OGTT)

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What is the significance of HBA1c?

Non-enzymatic glycation of hemoglobin (depends on plasma glucose levels)
Indicator of long-term glucose control (Over previous 3-4 months)
Poor blood glucose control (high HBA1c), higher risk of complications (microvascular and macrovascular)
Optimal blood glucose control reduces risk of complications
Used for diagnosis of diabetes mellitus – greater than 6.5%

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Summarize medical nutrition therapy

Medical nutrition therapy • Dietary modifications
Weight reduction
Exercise and lifestyle modifications
Oral hypoglycemic agents
Insulin injections (type 1 and in later stages of type 2 diabetes)

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What is medical nutrition therapy?

Life-long, multidisciplinary approach
Patient education and lifestyle modifications including families • Smoking cessation/ alcohol in moderation
Monitoring for Microvascular/Macrovascular complications • Metabolic control (Plasma glucose and HbA1c)
Eye exams for retinopathy, renal function assessment • Peripheral neuropathy, prevention of diabetic foot
Blood pressure management
Cardiovascular complications and lipid profile
Anthropometry (Height, weight and BMI)

What modifications to carbohydrates are done for diabetics?

High glycemic index foods replaced with foods that cause a slower increase in blood glucose (lower glycemic index)
Reduce refined carbohydrate (mono and disaccharide). Replaced by artificial sweeteners (non-caloric) like aspartame, sugar alcohols (xylitol)
Carbohydratecounting

What modifications to dietary fiber is made in diabetics?

Increase dietary fiber (whole grains, beans)
• Decreasesglycemicindex(slower glucose absorption)
• Improvessatiety(reducescalorie consumption)
• Reduces cholesterol absorption and improves blood cholesterol levels

What modifications to dietary lipids are made in diabetics?

Dietary lipid: Dyslipidemia and reduce cardiovascular risk
Low saturated fatty acids
No trans-fats
Reduction in dietary cholesterol (200-300 mg/day)
Lipid content 25-30% of total caloric consumption
Increase omega3: omega6 ratio improves cardiovascular health Dietary sodium restriction if hypertensive

How is weight managed for diabetics?

Weight Management:
• Prediabetes/overt diabetes: maintain weight and BMI (Ideal: 22-25)
• Weight reduction→ improvement in insulin resistance (Prediabetics can delay onset of type II diabetes)
• Better plasma glucose control, HbA1c, blood pressure control (critical for long-term management

What are physical and lifestyle modifications are done for diabetics?

Physical Activity and Lifestyle Modifications:
• Sedentary lifestyle risk factor for insulin resistance
• Physical activity improves insulin sensitivity via
• Increased metabolism and increasing lean body mass
• Increased GLUT-4 and increased glucose uptake
• Reducing visceral (central) obesity
• Improving blood pressure control
• Decreases serum TAG and improves HDL
• Half-hour moderate intensity exercise (5-6 times per week)
• Caloric restriction with exercise most beneficial
• Caution – Diabetics on insulin, signs of hypoglycemia, modify insulin dose and timing

Summarize the basis of pharmacotherapy for diabetics

• Drugs that increase insulin secretion (act on beta cells of pancreas to increase insulin secretion)
• Sulfonylurea • Incretins
• Drugs that improve insulin sensitivity (improve insulin resistance)
• Metformin – Decrease glucose output from liver and increase glucose utilization in
muscle
• Thiazolidinediones – act on adipose tissue via PPARG (peroxisomal proliferator activated receptor-gamma). PPARG regulates adipocyte differentiation and glucose homeostasis. Improves adipocyte insulin sensitivity
• Drugs which reduce dietary carbohydrate absorption – Alpha glucosidase inhibitors

Explain the impact of insulin therapy in diabetics

Recombinant human insulin
Type 1 diabetics: life-long insulin supplements
Type 2 diabetics: Insulin in later stages/elective surgery/infections
Standard vs intensive insulin therapy
Intensive insulin therapy – Rigorous control of plasma glucose –better HbA1c and lower risk of complications.
But, high risk of hypoglycemia due to insulin overdose
Standard insulin therapy – less rigorous control of plasma glucose and slightly higher HbA1c levels – higher risk of long-term complications.
But, lower risk of hypoglycemic episodes
Recognize hypoglycemia and immediate management

What are the normal blood glucose levels?

* Fasting: 70 – 100 mg/dL (3.9 – 5.6 mmol/L) | * 2 hrs postprandial: less than 120 mg/dL (< 6.6 mmol/L) • Prediabetic: 100-125 md/dl (3.9 – 6.9 mmol/L)

What is the glycemic range for hypoglycemia?

• Blood glucose level below 55 mg/dL (< 3.0 mmol/L) with adrenergic or neuroglycopenia symptoms.

What is the Special role of glucose in metabolic homeostasis?

Many cells depend on glucose for their metabolism (RBC, brain, retina as examples) 1. Insulin and glucagon are the main hormonal regulators of blood glucose levels and the release of insulin or glucagon responds directly to glucose molecules in the blood. 2. Glucagon, epinephrine, cortisol and growth hormone are often grouped as insulin counterregulatory hormones and are released to prevent hypoglycemia.

How does low blood glucose lead to release of insulin counterregulatory hormones?

These hormones are released by two overlapping glucose- regulatory systems: Glucagon is directly release by a-cells. 1 Hypothalamic glucoreceptors can trigger: 2 The release of ACTH and growth hormones from the anterior pituitary gland. ACTH stimulates cortisol release which leads to epinephrine secretion from the medulla. The secretion of catecholamines using the sympathetic autonomic nervous system.

What is the response to low blood glucose levels?

1. Less than 70 mg/dL: Increased release of: Epinephrine Glucagon Growth hormone Cortisol 2. Less than 55 mg/dL: Begin of adrenergic and neuroglycopenia symptoms. Transient hypoglycemia can lead to cerebral dysfunction. Severe prolonged hypoglycemia can cause coma and death.

What are the adrenergic symptoms of low blood glucose?

Adrenergic symptoms usually occur when the blood glucose level falls abruptly and epinephrine release is stimulated. Symptoms: anxiety, palpitation, tremors, sweating.

What are the neuroglycopenia symptoms of low blood glucose?

Neuroglycopenia symptoms usually occur from a gradual decline in blood glucose often below 40 mg/dL. The slow decline deprives the brain of glucose but fails to trigger the epinephrine response. Symptoms: headache, confusion, slurred speech and coma which can lead to death in prolonged hypoglycemia.

Hypoglycemia is when blood glucose falls below

55 mg/dL

Hypoglycemia is characterized by

1. CNS symptoms like confusion, aberrant behavior or coma. 2. A low blood glucose level of 55 mg/dL or below. 3. The fast relief of symptoms after the glucose levels are raised.

How is hypoglycemia treated?

Conscious patient: Oral consumption of glucose. Unconscious patient: Injection of glucagon or epinephrine to activate hepatic glycogen degradation and release of glucose into the blood.

What can lead to hypoglycemia ?

1. Insulin injection can cause hypoglycemia which is frequently found in diabetic patients. 2. Reactive postprandial hypoglycemia is transient and can occur after a carbohydrate-rich meal. 3. Hereditary diseases can cause hypoglycemia which needs specific treatment. 4. High alcohol intake can cause hypoglycemia due to reduced gluconeogenesis.

Explain alcohol related fasting hypoglycemia

Common in undernourished, longer fasting or dehydrated individuals after consumption of many drinks with high alcohol content. Alcohol metabolism in the liver uses enzymes that change many molecules of NAD+ to NADH during their reactions. Ethanol can lead to an abnormal high NADH/NAD+ ratio in the hepatocytes which reduces gluconeogenesis. Most individuals experience mild and transient fasting hypoglycemia which will disappear after food intake. Chronic intake of many drinks with high alcoholic content leads to an ongoing problem with fasting hypoglycemia.

Describe hypoglycemia due to insulinoma

Insulinoma is a tumor of the pancreatic islet cells that releases insulin. • Severe hypoglycemia may result in patients with an insulinoma due to excessive uptake of blood glucose into skeletal muscle and fat cells by GLUT-4. • Abnormal high level of serum insulin blocks the action of the insulin counter- regulatory hormones. • The blood contains high levels of insulin and C-peptide and elevated amounts of proinsulin.

What is Factitious hypoglycemia ?

Factitious disorders can be found in patients who simulate a disease or artificially induce clinical symptoms. For example, a non-diabetic individual with factitious disorder may obtain drugs for treatment meant for a diabetic patient and induces factitious hypoglycemia by using: 1. Insulin injection 2. Sulfonylurea tablets Blood is tested for insulin, C-peptide, proinsulin and sulfonylurea.

What are the causes of hypoglycemias?

1. Hypoglycemia due to insulinoma Tumor in the pancreas forms high levels of endogenous insulin. 2. Hypoglycemia due to high insulin Insulin injection (high insulin). Exaggerated postprandial response (high insulin). Factitious disorder (high insulin from insulin injection or sulfonylurea). 3. Hypoglycemia due to reduced gluconeogenesis Hereditary disorders. Alcohol induced during fasting hypoglycemia.

What are the causes of hyperglycemias?

Under secretion of insulin • Type I Diabetes Mellitus: can result from atrophy or destruction of b-cells of pancreas due to an immune response or viral infection. 2. Decreasedsensitivitytoinsulin • Type II Diabetes Mellitus: insulin resistance - more insulin than normal is needed for the insulin receptors to respond.