Week 3 - diabetes

Question 1

what is the first lifestyle recommendations made to patients newly diagnosed with T2 diabetes?

Answer 1

exercise

Question 2

Exercise benefits

Answer 2

In addition to the cardiovascular benefits, long term exercise promotes healthier skeletal muscle, adipose tissue, liver and pancreas function.
Facilitates improved glucose regulation

Question 3

Patients with diabetes are 2 to 4 times more likely than healthy individuals to suffer from cardiovascular disease. why?

Answer 3

Due to the metabolic complexity and underlying comorbidities of type 2 diabetes including obesity, insulin resistance, dyslipidaemia, Hyperglycemia, and hypertension.

Question 4

HbA1c

Answer 4

Elevated haemoglobin A1c (HbA1c) levels are predictive of vascular complications in patients with diabetes, and regular exercise has been shown to reduce HbA1c levels, both alone and in conjunction with dietary intervention.
RCTs- larger reductions in HbA1c were observed with more intense exercise, reflecting greater improvements in blood glucose control with increasing exercise intensity.

Question 5

Exercise and insulin

Answer 5

Laboratory experiments observed decreased fasting plasma insulin, a 45% increase in insulin-stimulated glucose disposal, and suppressed hepatic glucose production (HGP) during carefully controlled euglycemic hyperinsulinemic clamps.
- Although the metabolic benefits of exercise are striking, the effects are short-lived and begin to fade within 48 to 96 hours.

Question 6

American Diabetes Association (ADA) recommendations for exercise in type 2 diabetes:

Answer 6

1)Aerobic Exercise
Duration: At least 150 minutes per week of moderate to vigorous exercise.
Frequency: Spread over 3 to 7 days per week, with no more than 2 consecutive days without exercise.
Guidelines:
Daily exercise is recommended to improve insulin action.
For younger or more fit individuals, shorter durations (at least 75 minutes/week) of vigorous or interval training may be sufficient.
Can be done as continuous or high-intensity interval training (HIIT).
2. Resistance Exercise
Frequency: 2 to 3 times per week on nonconsecutive days.
Guidelines:
Involves 8 to 10 exercises, with 1 to 3 sets of 10 to 15 repetitions each.
3. Flexibility and Balance Training
Recommended 2 to 3 times per week, especially for older adults.
4. Supervised Training
Participation in supervised exercise programs is advised to maximize health benefits for individuals with type 2 diabetes.

Question 7

Aerobic exercise:

Answer 7

• Moderate to vigorous (65%–90% of maximum heart rate) aerobic exercise training improves VO2max and cardiac output, which are associated with substantially reduced cardiovascular and overall mortality risk in patients with type 2 diabetes.
• Aerobic exercise is a well-established way to improve HbA1c, and strong evidence exists with regard to the effects of aerobic activity on weight loss and the enhanced regulation of lipid and lipoprotein metabolism.
• report on 6 months aerobic exercise training in adults with T2DM found reductions in: HbA1c, fasting plasma glucose, insulin resistance, fasting insulin and systolic BP.
  Aerobic exercise improves glycaemic control, insulin sensitivity, oxidative capacity, and important related metabolic parameters.

Question 8

Resistance training:

Answer 8

Primary outcomes in studies evaluating the effects of resistance training in T2DM have found improvements that range from 10% to 15% in strength, bone mineral density, blood pressure, lipid profiles, cardiovascular health, insulin sensitivity, and muscle mass. As well as reduction in HbA1c
Lean body mass can increase
Improved insulin and glucose responses

Question 9

Combining aerobic and resistance training:

Answer 9

16 weeks of combined training led to significantly increased insulin-mediated glucose uptake compared with a group performing only aerobic exercise, reflecting greater insulin sensitivity.
Combined aerobic and resistance training markedly improved HbA1c

Question 10

High-intensity interval training (HIIT):

Answer 10

• HIIT increases skeletal muscle oxidative capacity, glycaemic control, and insulin sensitivity in adults with type 2 diabetes.
• A recent meta-analysis that quantified the effects of HIIT programs on glucose regulation and insulin resistance reported superior effects for HIIT compared with aerobic training or no exercise as a control. HIIT groups had a 0.19% decrease in HbA1c and a 1.3-kg decrease in body weight compared with control groups.
  A 6-week CrossFit program reduced body fat, diastolic blood pressure, lipids, and metabolic syndrome Z-score, and increased insulin sensitivity to glucose, basal fat oxidation, VO2max, and high-molecular-weight adiponectin.

Question 11

Tissue specific metabolic effects of exercise in patients with T2DM

Answer 11

Adipose Tissue (Fat)
Decreases: Inflammation, fat mass
Increases: Insulin sensitivity
Muscle:
Increases: Glucose uptake, glucose and fatty acid oxidation, insulin sensitivity
Liver:
Increases: Insulin sensitivity
Decreases: Hepatic glucose production, triglyceride accumulation
Pancreas:
Increases: Beta-cell mass, insulin production
Decreases: Glucagon levels
Circulatory System:
Decreases: Blood glucose, haemoglobin A1c, serum triglycerides, free fatty acids, blood pressure

Question 12

Skeletal muscle:

Answer 12

• Following a meal, skeletal muscle is the primary site for glucose disposal and uptake
• Peripheral insulin resistance originating in skeletal muscle is a major driver for the development and progression of type 2 diabetes.
• Exercise enhances skeletal muscle glucose uptake using both insulin-dependent and insulin-independent mechanisms, and regular exercise results in sustained improvements in insulin sensitivity and glucose disposal.
• Acute bouts of exercise can also temporarily enhance glucose uptake by the skeletal muscle up to fivefold via increased (insulin-independent) glucose transport. As this transient effect fades, it is replaced by increased insulin sensitivity, and over time, these 2 adaptations to exercise result in improvements in both the insulin responsiveness and insulin sensitivity of skeletal muscle.

Question 13

AMPK

Answer 13

• The fuel-sensing enzyme AMPK is the major insulin-independent regulator of glucose uptake, and its activation in skeletal muscle by exercise induces glucose transport, lipid and protein synthesis, and nutrient metabolism.
• AMPK remains transiently activated after exercise and regulates several downstream targets involved in mitochondrial biogenesis and function and oxidative capacity.
• In this regard, aerobic training has been shown to increase skeletal muscle mitochondrial content and oxidative enzymes, resulting in dramatic improvements in glucose and fatty acid oxidation and increased expression of proteins involved in insulin signalling.

Question 14

Adipose tissue:

Answer 14

• Exercise confers numerous positive effects in adipose tissue: reduced fat mass, enhanced insulin sensitivity, and decreased inflammation.
• Chronic low-grade inflammation has been integrally linked to T2 diabetes and increased risk of CV disease.
• Several inflammatory adipokines have emerged as novel predictors for the development of atherosclerosis, and fat-cell enlargement from excessive caloric intake leads to increased production of pro-inflammatory cytokines, altered adipokine secretion, increased circulating fatty acids, and lipotoxicity concomitant with insulin resistance.
• It has been suggested that exercise may suppress cytokine production through reduced inflammatory cell infiltration and improved adipocyte function.
• Levels of the key pro-inflammatory marker C-reactive protein is markedly reduced by exercise, and normalization of adipokine signalling and related cytokine secretion has been validated for multiple exercise modalities.

Question 15

Liver:

Answer 15

• The liver regulates glucose through gluconeogenesis and glycogen storage
• The liver is the primary site of action for pancreatic hormones during the transition from pre- to postprandial states.
• Insulin resistance is also present within the liver in patients with T2 diabetes.
• Impaired suppression of HGP by insulin is a hallmark of type 2 diabetes, leading to sustained Hyperglycemia.
• 7 days of aerobic training, in the absence of weight loss, improves hepatic insulin sensitivity.
• Hepatic AMPK is stimulated during exercise, suggesting that an AMPK-induced adaptive response to exercise may facilitate improved suppression of HGP.
• A longer 12-week aerobic exercise intervention reduces hepatic insulin resistance, with and without restricted caloric intake.

Question 16

Pancreas:

Answer 16

• Insulin resistance in adipose tissue, muscle, or the liver places greater demand on insulin secretion from pancreatic beta cells.
• For many, this hypersecretory state is unsustainable, and the subsequent loss of beta-cell function marks the onset of type 2 diabetes.
• Fasting plasma glucose, insulin, and glucagon levels are generally poor indicators of beta-cell function.
• It has been shown that a relatively short (8-week) HIIT program improved beta-cell function in patients with type 2 diabetes

Question 17

measurements for hepatic insulin sensitivity

Answer 17

hyper-insulinemic-euglycemic clamp technique, along with isotopic glucose tracers.
- More elaborate, magnetic resonance spectroscopy may also be used to assess intrahepatic lipid content, as its accumulation has been shown to drive hepatic insulin resistance.
- Indirect measures of hepatic dysfunction may be made from increased levels of the circulating hepatic enzymes alkaline phosphatase, alanine transaminase, and aspartate transaminase.

Question 18

Measurements of glucose homeostasis by the pancreas

Answer 18

• Clinical research studies typically use the oral glucose tolerance test and hyperglycaemic clamp technique

Question 19

Summary:

Answer 19

• Regular exercise: enhances glycaemic control, insulin signalling, and blood lipids, as well as reduces low-grade inflammation, improved vascular function, and weight loss.
• Both aerobic and resistance training promote healthier skeletal muscle, adipose tissue, liver and pancreatic function.
• Greater whole-body insulin sensitivity is seen immediately after exercise and persist for up to 96 hours.
• A discrete bout of exercise provides substantial metabolic benefits in diabetic cohorts: maintenance of glucose control and insulin sensitivity are maximized by physiologic adaptations that only occur with weeks, months, and years of exercise training.
• Exercise intensity, volume, and frequency are associated with reductions in HbA1c; however, a consensus has not been reached on whether one is a better determinant than the other.
• The most important consideration when recommending exercise to patients with type 2 diabetes is that the intensity and volume be optimized for the greatest metabolic benefit while avoiding injury or cardiovascular risk

Question 20

Diabetes

Answer 20

• Diabetes (diabetes mellitus) refers to several metabolic conditions characterised by chronic hyperglycaemia (raised blood glucose concentrations).
• Occurs when the body cannot produce any, or produces insufficient amounts of the hormone insulin, or because the body’s tissues become resistant to the effects of insulin.
• Major cause of morbidity- increasing risk of cardiovascular disease, eye disease, blindness, cancer, chronic kidney disease, neurological disorders, peripheral vascular disease in the lower limbs, pregnancy complications and adverse oral health

Question 21

diabetes diagnosis

Answer 21

• It has traditionally been diagnosed based on a fasting plasma glucose measurement or from an oral glucose tolerance test, in which 75g oral glucose load is consumed and plasma glucose concentrations are monitored for 2 hours.
• More recently it has been diagnosed based on glycated haemoglobin (HbA1c) concentrations.
• Glucose in the bloodstream bonds irreversibly with haemoglobin in proportion to average plasma glucose concentrations. As the life of RBC’s is approx. 3months, the HbA1c concentration represents a weighted average of plasma glucose concentrations over this period.
• Advantages of this method: fasting not required for measurement, time-consuming oral glucose tolerance test not required.

Question 22

Types of diabetes

Answer 22

T1DM
T2DM
Gestational (hyperglycaemia in pregnant women without a previous history of diabetes)
Maturity onset diabetes of the young (MODY- caused by single gene mutations affect insulin production (sometimes called monogenic diabetes)
Latent autoimmune diabetes in adults (LADA- occurs in adulthood which has characteristics of both type 1 & 2 diabetes – can be referred to as type ‘1.5’).

Question 23

Type 1 diabetes = insulin-dependent diabetes mellitus (IDDM):

Answer 23

• Caused by an autoimmune destruction of the pancreatic beta cells (in the islets of Langerhans).
• As a result the pancreas is nave to produce insulin (insulin must be injected not given orally because gastrointestinal enzymes would ingest it).
• Usually occurs before adulthood (Juvenile-onset diabetes).
• Associated with increased risk of both macrovascular disease (diseases if large blood vessels, principally CHD and stroke) and of microvascular complications (damage to small blood vessels – eyes (retinopathy), kidneys (nephropathy) and nerves of the hands, feet, arms and legs (peripheral neuropathy)).

Question 24

Type 2 diabetes = non-insulin-dependent diabetes mellitus (NIDDM):

Answer 24

• Characterised by insensitivity of cells in the body (primarily in skeletal muscle, liver and adipose tissue) to the effects of insulin – insulin resistance.
• This means that greater levels of insulin secretion by the pancreatic beta cells, leading to higher circulating insulin concentrations, are needed to maintain blood glucose concentration in the normal range.
• When beta cells become unable to maintain high level of insulin secretion needed to compensate for this insulin resistance, blood glucose levs rise leading to type 2 diabetes (Ryden et al 2013).
• Macrovascular complications can be evident in normoglycemic insulin restraint individuals, but microvascular complications only increase substantially with the onset of diabetes.
• Most common form – accounts for 90% of all cases worldwide

Question 25

What are the consequences of insulin resistance?

Answer 25

1) Glucose metabolism
2) Lipid metabolism and blood pressure
3) Insulin resistance in adipocytes make them insensitive to the antilipolytic (resisting the breakdown of fat) effects of insulin
4) Disturbances in many other body systems – ‘metabolic syndrome’
5) Metabolic abnormities

Question 26

Indications of insulin resistance:

Answer 26

One indication of insulin resistance is fasting hyperinsulinemia (high fasting insulin concentration) in the presence of either normal or elevated blood glucose concentrations.
Insulin resistance also leads to a larger postprandial rise In insulin concentrations, and both fasting insulin concentrations and postprandial insulin responses (often in response to a standardised 75g oral glucose load) can be used to assess insulin resistance.

Question 27

The gold-standard method for assessing insulin resistance

Answer 27

The euglycaemic hyperinsulinaemic clamp, which involves intravenous (via the vein) infusion of insulin at a predefined rate with glucose simultaneously infused at the rat needed to maintain euglycaemia (normal blood glucose concentration).
- In this test, a higher required glucose infusion rate indicates greater insulin sensitivity.

Question 28

Insulin resistance influences regulation of blood glucose concentrations in two ways:

Answer 28

1) Resistance of peripheral tissues (skeletal muscle) to the effects of insulin means that less glucose is cleared from the blood for a given concentration of insulin
2) Insulin resistance in the liver means that insulin is less effective at suppressing hepatic glucose production when this is metabolically appropriate (e.g., after a meal)
* Thus, insulin resistance can both prevent downregulation of glucose production by the liver and impair glucose clearance from the circulation into muscle.

Question 29

Insulins effect on lipid metabolism:

Answer 29

• Thus, when insulin resistance develops, insulin’s normal effects are impaired resulting in increased hepatic VLDL secretin, and decreased clearance of VLDL and (in the postprandial state) chylomicrons from the circulation, which results in higher plasma triglyceride concentrations.
• Consequently, there is increased neutral lipid exchange between triglyceride-rich chylomicrons and VLDL with cholesterol-rich high-density lipoproteins (HDL) and low-density lipoproteins (LDL).
• This depletes HDL of cholesterol and leads to small, dense LDL particles – a combination termed the ‘atherogenic lipoprotein phenotype’ – which is associated with increased CVD risk.

Question 30

Insulin resistance in adipocytes

Answer 30

, insulin resistance in adipocytes make them insensitive to the antilipolytic (resisting the breakdown of fat) effects of insulin.
- Thus, triglycerides within adipocytes are catabolised, leading to the release of non-esterified fatty acids (NEFAs) and glycerol into the circulation.
- These elevated NEFAs compromise the tissues’ ability to clear glucose, thereby exacerbating insulin resistance.

Question 31

‘metabolic syndrome’

Answer 31

clustering of metabolic dysfunction around insulin resistance

Question 32

Insulin resistance is mechanistically linked to a range of metabolic abnormalities including:

Answer 32

Endothelial dysfunction, Increased inflammation, Increased thrombotic risk, Androgen disturbances, Renal dysfunction,
Non-alcoholic fatty liver disease
Appetite dysregulation

Question 33

The current internationally agreed criteria for clinical diagnosis of metabolic syndrome is the presence of 3 out of the following 5 criteria:

Answer 33

1) Elevated waist circumference (with population and country specific definitions)
2) Elevated triglycerides ( ≥ 1.7 mmol l –1 )
3) Reduced HDL cholesterol (<1.3 mmol l –1 for men, <1.0 mmol l –1 for women)
4) Elevated blood pressure (systolic ≥ 130 and/or diastolic ≥ 85 mm Hg
5) Elevated fasting glucose (>5.5 mmol l –1 )

Question 34

Non-modifiable risk factors for type 2 diabetes:

Answer 34

Age
Sex (prevalence higher in men than women)
Ethnicity ( Afro-Caribbean or African American ethnicity have about twice the risk, and adults who are of South Asian origin have tow or three times the risk, compared with adults of white European ethnic origin)
Family history

Question 35

What is the most important modifiable risk factor for T2 diabetes

Answer 35

Obesity
- Substantial weight loss can lead to diabetes remission

Question 36

‘Adipose tissue overflow hypothesis’:

Answer 36

• This postulates that subcutaneous (under the skin) adipose tissue is the primary storage depot for fat, and once this becomes ‘full’, fat accumulating from positive energy balance spills over into visceral (around internal organs) and ectopic fat within the liver, pancreas and skeletal muscle.
  Individuals with high subcutaneous fat storage capacity can attain very high BMIs without accumulating substantial visceral and ectopic fat, and remain metabolically healthy.
  Whereas, individuals with the condition lipodystrophy (impaired ability to store subcutaneous fat), accumulate substantial visceral and ectopic fat with even modest weight gain, and develop severe insulin resistance and T2 diabetes.

Question 37

Physical activity and sedentary behaviour

Answer 37

Data indicates that the association between physical activity and risk of diabetes is partially independent of, and partially mediated by, the effects of physical activity on BMI.
In terms of potential strategies to reduce type 2 diabetes risk, focusing on reducing television viewing may be a stronger target than overall time spent sitting

Question 38

Muscle strengthening resistance exercise and risk of T2 diabetes:

Answer 38

In analyses controlled for adiposity, each standard deviation increase in muscular strength was associated with a 13% lower relative risk of type 2 diabetes.
* The available (but limited) evidence indicates that muscle-strengthening activity and aerobic PA appear to be independently associated with T2 diabetes risk.

Question 39

Cardiorespiratory fitness and muscular strength as risk factors for T2 diabetes:

Answer 39

Each 1-MET increase in cardiorespiratory fitness was associated with 10% lower risk of developing type 2 diabetes.
Fitness and BMI are independently associated with T2 diabetes and, while being fit is associated with a substantially lower diabetes risk in the overweight and obese, there is still substantial excess risk amongst those who are fit but overweight or obese.
In humans, VO2 max is a strong predictor of whole-body insulin sensitivity.
Mechanically, the link between cardiorespiratory fitness and insulin resistance and diabetes risk is likely to be mediated via effects on skeletal muscle mitochondrial function, which has been strongly implicated in the pathogenesis of insulin resistance and T2 diabetes.
One study found that patients with type 2 diabetes had smaller mitochondria than a lean non-diabetic control group (lower mitochondrial oxidative capacity could lead to an accumulation of intramuscular lipid intermediates which impair insulin signalling).

Question 40

Lifestyle intervention in the management of type 2 diabetes:

Answer 40

A large body of evidence from intervention studies demonstrates that both aerobic and resistance training are effective at improving glucose control, reducing HbA1c concentrations, and improving markers of metabolic health amongst people with T2 diabetes.
The American Diabetes Association recommends that people with type 2 diabetes undertake daily exercise, and ideally perform both aerobic and resistance exercise training for optimal glycaemic and health outcomes

Question 41

Summary:

Answer 41

• Insulin resistance can lead to a cluster of adverse changes to glucose metabolism, lipid metabolism, vascular function and inflammation which are associated with increased microvascular disease risk.
• Obesity is the important modifiable risk factor for type 2 diabetes, and substantial weight loss in people with type 2 diabetes can put disease into remission.
• Prospective observational studies demonstrate an association between low levels of physical activity, low cardiovascular fitness and low muscular strength and increase risk of type 2 diabetes.
• Randomised controlled rials of lifestyle interventions incorporating physical activity and dietary change demonstrate that they are effective at preventing type 2 diabetes. Longer-term follow-up in these trails indicates that this benefit persists for up to 30 years and may also extend to reductions in risk of microvascular complications and mortality.
• Physical activity in patients with type 2 diabetes improves glycaemic and other health outcomes, with a combination of aerobic ad resistance exercise inducing larger benefits to HbA1c reduction than either type of exercise alone.