Write about the current thinking behind the molecular basis of insulin resistance in type 2

diabetes.

Type 2 diabetes
 Non-insulin dependent diabetes mellitus (NIDDM)
 Gradual and slow onset
 Can be asymptomatic and difficult to diagnose
 Signs: commonly obese
 C-peptide is detectable (because you are producing insulin in type 2)
 Little tendency to ketosis
 No autoimmunity markers
 Insulin resistant
 Treatment: diet changes may be sufficient. Insulin may be needed in some cases.
Sulphonylureas may be effective.

Risk factors
 Obesity
In both type I and type II
 Hyperglycemic
 After oral glucose tolerance test (OGTT) their glucose remains high
Ceramides are a family of waxy lipid molecules. A ceraminde is composed of a spingosine
and a fatty acid.

In type II
 GLUT 4 transporters aren’t being recruited, problem with signal transduction

Biochemical basis of diabetic complications

A role for visceral fat in insulin resistance
1. Increased circulating fatty acids resulting in continual fatty acid oxidation- pyruvate
dehydrogenase – Randle
2. Increased circulating TNF-α interferes with insulin receptor signaling
3. Increased fat in muscle

Current thinking behind molecular basis of T2D

Overview - https://diabetes.diabetesjournals.org/content/53/suppl_1/S60

1. Randle …increased circulating fatty acids results in contiual fatty acid oxidation.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739696/

Thrify gene hypothesis

Are Pima Indians better at storing food because they have more famine in their ancestry?

Lipotoxic model
 A high acetyl coA will inhibit pyruvate dehydrogenase.
 Randle demonstrated that impairment of glucose metabolism by fatty acid (or
ketone body) oxidation was mediated by a short-term inhibition of several glycolytic
 steps, namely glucose transport and phosphorylation, 6-phosphofructo-1-kinase
(PFK-1), and PDH.

TNF-alpha
 TNF-alpha is produced by fat cells and by macrophages in your fat cells.
 TNF-alpha interferes with insulin signaling.
 LPS is a major trigger of TLR4 which stimulates release of TNF-alpha.

PPAR- γ
https://diabetes.diabetesjournals.org/content/53/suppl_1/S60
 Peroxisome proliferator-activated receptor (PPAR)-γ is a nuclear hormone receptor
that comprises an agonist-dependent activation domain (AF-2), DNA binding domain,
and agonist-independent activation domain (AF-1).
 It is expressed predominantly in adipose tissue but is expressed in other tissues as
well.
 Patients with a dominant-negative mutation in the PPAR-γ gene show severe
hyperglycemia, which provides a genetic link between PPAR-γ and type 2 diabetes .
 Essentially tiggering PPAR- γ receptors on white adipose tissue (WAT) encourage
uptake of circulting fats and increases WAT mass.
 So PPAR- γ reduces blood levels of fat.

CAPN10
 CAPN10 is a calcium-activated neutral protease that is a member of the calpain-like
cysteine protease family.
 Variation in the non-coding region of the CAPN10 gene is associated with a
threefold increased risk of type 2 diabetes in Mexican Americans.
 However, in European populations, polymorphisms in CAPN10 are less contributory
to type 2 diabetes than other recently discovered genes.
 Genetic variants in CAPN10 may alter insulin secretion or insulin action as well as
the production of glucose by the liver.

TCF7L2
Transcription factor 7- like 2
 TCF7L2: a transcription factor in beta-cells.
 Silencing reduces insulin release.
 15% of Europeans carry two copies of the abnormal gene and have double the lifetime
risk of developing T2D.

The hexosamine biosynthesis pathway (HBP)

 This leads to the formation of UDP-N-acetylglucosamine (UDP-GlcNAc).
 There is considerable evidence from adipose tissue and skeletal muscle to support the
hypothesis that elevated extracellular glucose leads to excess flux through the HBP.
 The HBP gained prominence in the field of diabetes when Marshall et al., found that
by inhibiting the rate limiting enzyme glutamine:fructose-6-phosphate
amidotransferase (GFAT), they could reverse glucose- induced cellular insulin
resistance.
 It has been shown that glucosamine (which is taken up by cells via glucose
transporters) induces insulin resistance (distal to GFAT).
  McClain and colleagues demonstrated that overexpression of GFAT leads to skeletal
muscle and adipocyte insulin resistance.
 GFAT causes glycosylation. Over-glycosylation can affect recruitment of the GLUT 4
transporters.

Exercise - https://diabetes.diabetesjournals.org/content/53/suppl_3/S67
 Exercise uses up ATP, producing more cAMP.
 This activates AMPK, which turns turns on catabolic processes and turns off anabolic
processes and causes recruitment of GLUT4 to the plasma membrane.
 The beneficial effects of exercise for T2D are mediated by AMPK.
 Moreover, metformin, used as an antidiabetic agent for >50 years, has recently been
shown to be an inhibitor of respiratory chain complex 1, which exerts some of its
effects through an inhibition of mitochondrial oxidative metabolism and activation of
AMPK

Ceramides - https://www.nature.com/articles/srep41231
 Produced from palmitate and serine.
 Over-production of ceramide can have detergenet effects on cells and can damage
mitichondria.
 The primary mechanism through which ceramide promotes insulin resistance is by
inhibiting the activity of Akt/PKB, which is an essential facilitator of glucose transport
into the cell.
 Ceramide activates PP2A, which inhibits the action of Akt/PKB by impairing Akt
serine phosphorylation (PP2A dephosphaorylates and inactivates Akt).
 The result of this inhibition is decreased translocation of glucose transporter type 4
(GLUT4) to the plasma membrane and hence decreased uptake of glucose. 

Insulin signaling – reminder from last year

https://drive.google.com/file/d/194a6eGcePorvHcemlGkZYHI_6y8U3V-C/view?usp=sharing
*One of the things Akt does is it inhibits AS160 via phosphorylation. AS160 is a negative
regualtor of GLUT4 translocation. So when AS160 is inhibited, GLUT4 receptors can
translocate to the cell membrane and allow glucose entry.

https://care.diabetesjournals.org/content/27/10/2450
 Adiponectin and resistin are adipose tissue-derived proteins with antagonistic
actions; adiponectin has insulin sensitive properties while resistin is involved in the
development of insulin resistance.
 Adiponectin, an adipose-specific protein, is found in high concentrations in the
peripheral circulation, and its circulating levels are decreased in obesity and type 2
diabetes.
 Adiponectin levels are inversely associated with central or overall adiposity, as well
as hyperlipidemia and insulin resistance independently of BMI.
 Resistin levels have been reported to be markedly elevated in obese mice and to be
decreased by insulin sensitizers, such as rosiglitazone. 

Free fatty acid levels and AMPK

  In adipose tissue, high concentrations of saturated free fatty acids such as palmitate
lead to lower activity of AMP-activated kinase (AMPK), a central regulator of energy
biosynthesis and lipid metabolism, which leads to defective autophagy of
mitochondria ('mitophagy').

Gut flora and T2D

 The gut microbiome may be responsible for the accumulation of BCAA metabolites in
the serum of obese individuals, leading to insulin resistance.
Drugs
Sulphonylureas e.g. Glibenclamide, inhibit ATP sensitive potassium channels in beta cells
and force beta cells to produce more insulin.

Drugs Metformin
 The glucose-lowering, insulin-sensitizing agent metformin works mainly by reducing
gluconeogenesis and opposing glucagon-mediated signalling in the liver and, to a
lesser extent, by increasing glucose uptake in skeletal muscle
 The primary site of metformin action is the mitochondrion
 Metformin affects lipid metabolism primarily via 5′-AMP-activated protein kinase
(AMPK) activation