Insulin Resistance

2022-05-03: reference:

Insulin Resistance/Sensitivity #

• Diabetes mellitus and the risk of dementia
  • Diabetes is a risk factor for stroke.
• Pituitary Contents of Beta-Endorphin, Dynorphin, Substance P, Cholecystokinin and Somatostatin in Rats with Streptozotocin-lnduced Diabetes
  • Decreased Substance P in anterior and ’neurointermediate’ lobe of the Pituitary Gland; Cholecystokinin, somatostatin, dynorphin in NIL, and increased Dynorphin in anterior lobe. All these changes were reversible with Insulin treatment!
• Hemoglobin HgBA1c - measures average blood sugar over 2-3 month period. Normal is <6% and gets to as high as 14%..
• The dark side of insulin: A primary autoantigen and instrument of self-destruction in type 1 diabetes

Pharma #

• Higher mortality, more heart disease and death, hypoglycemia, and even weight gain. Probably does not decrease microvascular disease (retinopathy, etc.)
  • Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial (Ismail-Beigi et al. 2010)
    • Intensive therapy did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of albuminuria and some measures of eye complications and neuropathy.
    • Microvascular benefits of intensive therapy should be weighed against the increase in total and cardiovascular disease-related mortality, increased weight gain, and high risk for severe hypoglycaemia.
• Long-term prognosis of diabetic patients with myocardial infarction: relation to antidiabetic treatment regimen. The TRACE Study Group (Gustafsson 2000)
  • Diabetic patients treated with oral hypoglycaemic agents or insulin, but not those treated with diet alone, have a significantly increased mortality following acute myocardial infarction compared with non-diabetic patients
• Effects of intensive glucose lowering in type 2 diabetes (Gerstein et al. 2008) death from heart disease
  • As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events.

Circadian Rhythm #

• Circadian clocks and insulin resistance - super comprehensive
• Fatty Acids, Obesity, and Insulin Resistance: Time for a Reevaluation
• https://raypeatforum.com/community/threads/tyw-said-something-that-makes-alot-of-sense.15816/
  • You still want fatty acid oxidation to match serum levels, or else the accumulation will impair insulin metabolism.
  • Diurnal variation of the human adipose transcriptome and the link to metabolic disease
    • Genes for burning fat, as opposed to storing it, are higher in the morning:We hypothesize that the diurnal transition of the expression of energy metabolism genes reflects the shift in the adipose tissue from an energy-expending state in the morning to an energy-storing state in the evening.
      • ‘Fuel accumulation’ genes rise (which includes GLUT1, 3, 5, 14 but not 4 and 2 interestingly which saw no effect.) No fatty acid synthase correlation either.
    • The diurnal transition was delayed by fasting and treatment with sibutramine.
    • An in silico comparison of the diurnal signature with data from the publicly-available connectivity map demonstrated a significant association with transcripts that were repressed by mTOR inhibitors
      • Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity
        • Protected against obesity owing to enhanced β-oxidation. On HFD, levels of glucose and FFA still rise, resulting in insulin receptor desensitization, but the loss of negative feedback loop from S6K->IRS1, blunting S307/S636/S639 phosphorylation
        • increased expression PPAR-δ, PPAR-β, PGC-1α, UCP3 and CPT1 (carnitine palmitoyltransferase.
  • Rev-Erb α peaks around 10am-12pm. Rev-Erb β peaks around 2-4 hours later. High
  • Fatty acids are always the preferred substrate in the heart and other smooth skeletal tissue. Glucose is preferred in the liver and brain, at least to the extent that it doesn’t follow high FFA leading to preferential use of FAO over carbs.
  • The nuclear receptor REV-ERB is required for the daily balance of carbohydrate and lipid metabolism
    • In Rev-Erbα (-/-) mice, they had 2.5-fold increased adiposity, 10% hyperglycemia without insulin resistance (tf?). Lipoprotein lipase is 2x upregulated in muscle and adipose tissue. CLOCK upregulated 2-fold, and can transactivate Lpl.
  • Or how about take an obese person, put them on a ketogenic diet, induce physiologic insulin resistance, which thereby prevents net ingress of calories into fatty tissue, thereby causing easy loss of that fatty tissue. ie: When trying to lose weight, it is a good thing to be insulin resistant in fat tissue. Insulin is a signal to “put energy into the cell”. Why do you want to put energy into fat cells when trying to lose fat?
    • Saturated Fats cause ROS production in adipocytes, increasing PPAR-γ. PUFAs make adipocytes insulin sensitive, allowing fat to stream in, as opposed to increasing number of fat cells.