Diabetes

Definition / Prevalence

Group of metabolic diseases characterised by hyperglycaemia resulting from defects in insulin secretion/action WITH long-term complications

CHRONIC ILLNESS which needs lifelong support

  • Diabetes UK estimates 4 mil people have diabetes (2018)


  • £1 million an hour NHS costs

DIAGNOSIS

DIABETES: Dysregulated insulin secretion or action which results in an inability to regulate blood glucose.


Classification:


  • Type 1: Insulin deficiency - lose ability to MAKE insulin - autoimmune - 10% diabetes cases
  • Type 2: HETEROGENOUS - Insulin Resistance - Lose ability to RECOGNISE insulin with elements of insulin deficiency - 90%
    • Insulin resitance in peripheral tissues AND/OR impaired beta-cell secretion of insulin.

Other types:

  • Pancreatic / drug induced / infections / gestational

YOU CAN HAVE TISSUE SPECIFIC IR

FULL DIABETES

  • Fasting plasma glucose >7.0 mmol/L
  • 75g ORGTT > 11.1 mmol/L
    HbA1c > 6.5% on two occasions (split by 3 months)

PREDIABTES

  • HbA1C > 5.7%
  • FPG > 5.6 mmol/L

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TYPE 1


  • Usually occurs in young age (puberty) <40
  • Weight loss
  • Hyper glycaemia
  • Polydipsia / Polyuria / Ketonuria

TYPE 2


  • Usually >40 years
  • Progresive
  • In context of met syndrome

Lifestyle MANAGEMENT

TYPE 1

  • DIETARY ADVICE + EDUCATION


    • Curriculum delivered by trained educators and quality assured


      • DAFNE (Type 1)

    • Avoid sugary foods / 3 meals a day / wholegrains / starchy food / less salt / less fat / less alcohol / exercise


  • ALCOHOL


    • Glucose load varies and can easily lead to hypoglycaemia

  • EXERCISE


    • Can be useful to manage blood sugars
    • Weights can lead to adreneline - hypoglycaemia

TYPE 2


  • Weight loss
  • Low carbohydrate diet
  • Low GI diet can reduce HbA1c (0.5%)
  • Dietary Fibre
  • Reduce Saturated Fat for polyunsaturated fat
  • Increase Physical Exercise (30 -60 minutes of exercise)
  • Reduced smoking
  • Reduce salt

Medical Management

Type 1

  • Insulin Pen
  • Insulin Pump
    • Long acting insulin (background)
    • Short acting insulin (to match meals)
      Insulin dose is dependent on diet
  • Islet / pancreas transplant

There are lots of different drugs


  • Increase insulin secretion (GLP-1 Agonists)
  • Decrease glucose production
  • Slow CHO digestion
  • Increase insulin sensitivity
  • Increase glucose urinary excretion (SGLT2 Inhibitors)
    .
  • BARIATRIC SUGREY - WEIGHT LOSS
  • Self-monitoring

Physiology

GENETICS

Talmud 2010 - using genetics with non-genetic risk factors to predict diabetes

  • Used the Framingham risk scores (odd that the risk score doesn't include physical activity)
  • Used 20 genetic risk factors (0-40 risk alleles)
  • COHORT STUDY
    • 5.5K people, 303 developed T2D in 10 years
    • use baseline info and genetics
  • Without adjusting for weighting of SNP - FOUND NO SIGNIFICANT RISK

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  • Maternally expressed transcription factor KLF14 but only expressed in adipose tissue BUT causes transcription factors to bind in various places in adipose tissue across the genome and change regulation. PROTECTS FORM T2D BY SHIFTING FAT DISTRIBUTION

BUT:

  • SNPs only adjust account for 10% BUT MZ IS 70%
  • SNPs might not be the causal variants
  • Need larger sample sizes
  • Rare variants not yet tested
  • Resilience not tested
  • Physical activity not accounted for
  • GENE-ENVIRONMENT NOT INCLUDED

Glucose -> ATP -> Increased intracellular calcium -> Insulin release from cell.

Insulin then acts on receptors (e.g. GLUT4) in liver, skeletal muscle, and adipose tissue


AND SHUTS DOWN GLUCONEOGENESIS & GLYCOGENOLYSIS

Increase in GLUT4 activity in fat and muscle/GLUT2 in liver -> more glucose absorbed -> more glycogen/protein/lipid synthesised

IR -> receptors do not respond to insulin


YOU CAN HAVE TISSUE SPECIFIC IR

Glucose is not absorbed and remains in bloodstream -> glycogen/protein/lipid not produced.
.
IR can be induced by high levels of fatty acids or centralised obesity and increased adipokine release.

38 SNPs have been found - but no causal variant yet. BUT there are some monogenic forms.

rs4731702 effect on KLF14 a master trans-regulator - also associated with T2D and HDL cholesterol

High heritability - but SNPs only account for 20% risk - IMPORTANCE OF ENVIRONMENT / V. COMPLEX DISEASE

Beta-cell dysfunction

Increased central adiposity

  • This occurs as a consequence of the imbalance between
    maintained (or increased) food intake and reduced physical
    activity
  • Also, reduced oestrogen and testosterone levels that occur
    with ageing contribute to the increased visceral fat mass
    (oestrogen and testosterone increase lipolysis)
  • Expanded adipocytes secrete adipokines, such as TNFα -
    obese people have chronically elevated TNFa levels
  • IN ANIMALS TNFa is associated with:
    • reduced GLUT4 expression.
    • increased blood glucose
    • increased fasting plasma insulin
    • decreased insulin sensitivity

Increased free fatty acids levels - saturated fat.

  1. FFAs activate inflammatory signalling, decrease mitochondrial
    function and stimulate accumulation of DAG and reactive oxygen species (ROS)
  2. Increased DAG, via de novo synthesis or through mitochondrial dysfunction, activates PKC isoforms
  3. FFAs stimulate Toll-like receptor 4 to activate JNK and IKKb, which are also activated by increased ROS
  4. PKC, JNK and IKKb phosphorylate IRS1/2 on serine residues to inhibit insulin receptor interaction
  5. Decreased IRS1/2 tyrosine phosphorylation results in
    reduced insulin signalling.
  • These kinases increase serine phosphorylation of IRS proteins -> insulin resistance

Decreased Skeletal Muscle Mass

  • Mitochondria in aged skeletal muscle produce less ATP and
    more ROS, promoting oxidative stress and insulin resistance
  • This reduces the rate of calories used by the body and
    exacerbates the problems associated with increased
    adiposity

Impaired β-cell stimulus-secretion coupling

  • Increased ROS generation, decreased ATP synthesis and
    decreased [Ca2+]
  1. In normal mitochondria oxidation of NADH and FADH2 drives ATP synthesis.
  2. β-cells have very low levels of SOD and catalase so are susceptible to damage when ROS levels are
    abnormally high.
  3. Increased glycolysis under hyperglycaemia overloads the mitochondria driving increased ROS generation
  4. Impaired b-cell mitochondria function results in decreased ATP generation

Ageing leads to:

  • Islet mitochondria malfunction
  • Reduced Ca2+ entry and mobilisation from endoplasmic reticulum stores
  • Impaired Ca2+ in response to glucose

Islet amyloid deposition and increased β-cell apoptosis


  • Amyloid deposition is commonly seen in T2D.
  • Amyloid is the trigger for a protein complex called the inflammasome that leads to the production of the proinflammatory agent IL-1b, which can induce β-cell apoptosis


  • Protein misfolding and ER stress could also lead to cell apoptosis

Reduced beta-cell proliferation

  • Healthy beta cells can respond to insulin resistance by increasing proliferation
  • BUT THIS ABILITY DECREASES IN AGE.

HYPERGLYCAEMIA EFFECTS

Generation of ROS

  1. Glucose increases mitochondrial OXPHOS leading to increased electron leakage and production of superoxide radicals.
  2. Mitochondrial SOD converts superoxide to hydrogen peroxide, which generates highly reactive hydroxyl radicals which damage all macromolecules. CAUSES APOPTOSIS.

Glycation of Proteins

  1. Glycation is non-enzymatic attachment of sugars such as
    glucose and fructose to amino groups of cellular proteins e.g. haemoglobin, collagen, elastin
  2. Early glycation products combine to form complex cross-linked structures termed advanced glycation end-products (AGE)
  3. Breakdown products of AGEs are usually cleared from
    plasma, but impaired renal function in diabetes leads to
    their accumulation.
  4. When AGEs bind to receptors (become RAGEs) -> increase ROS production + increased inflammation and cell apoptosis.

AGE accumulation by cells -> decreased survival and increased vascular complications.


ALSO IS ASSOCIATED WITH WRINKLES, MODIFIED BLOOD CELLS AND STIFFENED ARTERIES.

Activation of Protein Kinase C

  • Increased glycolysis generates DAG, which activates PKC
  • PKC promotes cellular dysfunction through the production
    of growth factors and other signalling molecules

Activation of Polyol Pathway (sorbitol and fructose)

  • Glucose is reduced to sorbitol by aldose reductase
  • Sorbitol does not cross cell membranes so it accumulates
    intracellularly
  • Sorbitol can damage cells through its osmotic effects as it breaks down slowly; high concentrations cause
    swelling of the lens and retinal pericyte damage
  • Sorbitol dehydrogenase oxidises sorbitol to fructose, which
    promotes glycation of intracellular proteins

Calorie Restriction

IN YEAST:

  • Under conditions of unrestricted food intake NAD+ is required for Sir2 activity through NADH synthesis during glycolysis
  • Calorie Excess - Sir2 activity is low because glycotic pathway is high.
  • CALORIE RESTRICTION - less glucose (in theory) - more NAD+ is available to Sir2 - Sir2 activation can increase lifespan

IN MAMMALS:

  • Inactivation of the insulin/IGF-1 receptor pathway promotes longevity in mammals through increased activity of FOXO1.
  • SIRT1 activation induces lifespan extension through deacetylating and activating FOXO1.

SIRT1

  • SIRT1 is regulated positively by CR and SIRT activating compounds and negatively by SIRT inhibitors.
  • SIRT1 activation induces survival of cardiomyocytes, protects neurons from cell death, and increases insulin secretion by repressing the mitochondrial uncoupling protein 2 (UCP2) in b-cells.
  • SIRT1 decreases white adipocyte tissue formation through repression of PPARg and promotes gluconeogenesis in response to fasting through PGC‐1α.
  • It also stimulates mitochondrial biogenesis in the brown adipose tissue (BAT) and the muscle through activation of PGC‐1α.

DIET AND T2DM DEVELOPMENT


  • Most research on diet is insulin sensitivity
  • Insulin secretion is much harder to study .
    .
  • Weight loss (rapid and significant (10%)) improves beta-cell function – but effect of weight gain on beta-cell function less well delineated.

NORMAL: High Insulin Sensitivity, Low Plasma Glucose, Low Plasma Insulin
PREDIABETES: Low Insulin Sensitivity, Mid plasma Glucose, High Plasma Insulin
DIABETES: Low Insulin Sensitivity, High Plasma Glucose, Low Plasma Insulin


IN DIABETES YOU LOSE THE INCRETIN EFFECT


  • Prediabetes can either lead to impaired glucose tolerance (IR in Liver) OR impaired fasting glucose (IR in Muscle)

IS AGE A NON-MODIFIABLE RISK FACTOR?

WEIGHT
BMI

  • Relative risk of diabetes increasing as BMI increases >23
  • 2% prevalence in people with a BMI <25 kg/m2
  • 13% in those with a BMI > 35 kg/m2
  • 1kg increase in weight increases the risk of diabetes by 4.5-9%

BUT THESE COHORT STUDIES DO NOT ACCOUNT FOR HEALTH BEHAVIOURS

  • BODY FAT PERCENTAGE / CENTRAL ADIPOSITY MORE USEFUL.

FAT INATKE

  • Effect of type of fat on glucose concentrations or insulin sensitivity not clear:
    • The best evidence is for n-6 PUFAs (Nurses Health Study)
    • Saturated fat - No effect?
    • Monounsaturated fats – no strong evidence (KANWU study) but difficult to evaluate in cohort studies.
    • Omega-3s: no effect (easier to study in cohort studies)
  • Methodology: IVGTT, hyperinsulinaemia-euglycaemic clamp, insulin concentrations.
  • Duration of diet?
  • Rest of diet? Refined CHO/fibre etc.
  • PREDIMED: Read!!!! (and all supplementary data: 25+ page) Diabetes Care, 2011.
  • Effects of Saturated Fat, Polyunsaturated Fat, Monounsaturated Fat, and Carbohydrate on Glucose-Insulin Homeostasis: A Systematic Review and Meta-analysis of Randomised Controlled Feeding Trials, July 19, 2016, PLOSOne.
  • Some evidence for n-6 fats, NO EVIDENCE FOR n-3 FATS.

CHO

  • Quality matters:
    • Glycaemic index: low GI association with reduced T2D incidence.
    • Total carbohydrate not linked.
  • Added sugar – sucrose
    • Data not consistent at all.
    • Sucrose in liquids appears to have greatest effect (Malik, Circulation, 2010, Te Morenga, SACN - SUGAR TAX - but seems to sucrose - fructose - DNL in liver - T2D incidence).
    • If effect is real – likely at high concentrations.
    • Interventional studies show impaired glucose regulation at ~25%kcal from sucrose (Kimber Stanhope’s work)

FIBRE

  • In interventional studies – soluble (viscous fibre) reduces post-prandial glucose concentrations (guar gum, pectin).
  • BUT, in cohort studies – it is cereal fibre which is consistently negatively associated.
  • In diabetes prevention studies fibre is associated with lowering risk of T2D (but again cannot prove causality)
  • Critical issues: solubility/fermentability/insoluble (beware of terms soluble & insoluble – mentioned here as used in older and epidemiological literature)
  • FELDMEN 2017 - Fibre significantly associated with reduced T2D risk. - BIG COHORT 10 YR FOLLOW-UP.
  • Difficult to define as different fibres have different physico-chemical properties.

  • Hypothesis: Fermentation of fibres by gut bacteria > production of short chain fatty acids > short chain fatty acids may:


    • Act directly on beta-cell to increase insulin secretion (FFA2 receptor)
    • Acetate in particular may help increase fat oxidation in muscle and change insulin sensitivity (See Denise Robertson’s work).

  • Hypothesis: incretin effect

  • Hypothesis: fibres slow gastric emptying, reduce glucose absorption and “protect” the beta-cell….
  • Hypothesis: other proposed links include reducing inflammation, and potentially via weight loss or prevention of weight regain (but evidence not strong).

Dairy

  • Meta-analyses:
    • Fairly consistent inverse relationship
      • Risk Ratios:
        • 0.86 (CIs: 0.79-0.92) (Tong 2011)
        • 0.92 (CIs: 0.86-0.97) (Elwood 2008)
        • 0.73 (CIs: 0.54-0.97) (Malik 2011)
      • Dose response relationship?:
        • One serving ↓ risk by 4-9% (Tong, Elwood)

  • Fermented?


    • Inter99:
      • Total dairy: OR 0.95 (CI: 0.86-1.06)
      • Fermented: Inverse assoc: plasma glucose and HbA1c
    • EPIC:
      • Total dairy: HR: 1.01 (CI: 0.83-1.34)
      • Fermented: HR: 0.88 (CI: 0.78-0.99)

  • No long-term trials with diabetes incidence as outcome

  • 12 RCTs investigating dairy on glucose and insulin in people with T2D
    • No consistent effects on glucose
    • Insulinotrophic?
      • Milk and cheese, but not yoghurt
    • Methodological limitations
      .
      Lactose - Low glycaemic
      Calcium - Insulin signalling in skeletal muscle
      Vitamin D - Insulin secretion / Insulin sensitivity
      Milk proteins (casein, whey) - Insulin secretion?, lower glucose levels?
      Cultured dairy - Gut microbiota
      .
      Saturated fats
    • Pentadecanoic Acid (C15:0)
    • Heptadecanoic Acid (C17:0)
      Trans fat
    • Trans-palmitoleic acid (trans 16:1n-7)

PREVENTION

NHS England just commenced NHS diabetes prevention program.

  • 20,000 people to be enrolled in first year
  • 100,000 every year thereafter.
    .
  • Series of long-term clinical trials
  • Lifestyle aimed at modest weight loss
  • Prevents up to 2/3 cases of diabetes
    .
  • US RCT found More effective than metformin - Diabetes prevention 2002
  • Finnish trial 2006 - Intervention more effective than control - maintained after 8 years follow-up.
    .
  • Most focus on weight loss and increased physical activity and fibre. (Interesting that Japanese want people to reduce eating out).

Dietary fibre:

  • Low energy density, and GI (EPIC study)
  • Reduce post-prandial absorption?
  • Cereal fibres have strongest association (NHS, EPIC).
  • Fermentable?

Weight loss is one of the main prevention strategies but can still maintain lower risk of T2 even after weight gain.

WEIGHTLOSS

Reverses ALL THIS ->

  • Reduces ectopic fat, esp liver and visceral fat -> Improves insulin sensitivity
  • Reduces circulating free fatty acids, and lipid intermediates -> Improves sensitivity & secretion?
  • Reduces adipokines - inflammation? -> Improves sensitivity & secretion?