I think coming back to the view of insulin resistance as an early symptom (preceded by hyperinsulineme but with normal glucose levels) of energy excess ties this all together. All this is from "from Obesity to Type 2 diabetes", details are probably wrong since its been a few yrs since I read it. This also ignores the role of the liver.
Basic logic is:
1. all humans (excepting those w/ rare diseases of fat cell differentiation) have a capacity for enegy buffering/storage because this is adaptive and a generally well-preserved trait in other animals.
2. in times of caloric excess, we increase fat deposition to store excess calories. This is mediated substantially through insulin. Biochemically, you'd see this with rising levels of insulin hormone production, with preserved/normal blood sugar levels.
3. Different people have differing capacities for insulin hormone production and different levels of fatness at which their capacity for energy storage becomes more resistant.
4. At this point, glucose levels start to rise, as insulin resistance rises and insulin hormone levels approach their max. This is prediabetes. At this point, these higher blood glucose levels are neccesary to keep driving calories into fat cells, even as those fat cells start to signal their full through insulin resistance.
5. At some point, your insulin levels can't rise further, and glucose levels reach "diabetic levels".
6. You have several therapeutic options.
A. Raise how much fat you can carry (thiazolidinediones do this)
B. Increase insulin production (exogenous insulin, sulfonyureas)
C. Reduce sugar intake (acarbose)
D. Reduce calorie intake (weight loss, GLP-1 agonists)
E. Reduce hepatic glucose output (Metformin)
From that perspective, it is easy easy to see why weight loss can so rapidly normalize symptoms. It is treating the fundamental underlying driver. Even mild weight loss can quickly move your equilibrium back to within-buffering range.
Further caveats: ignores pancreas burnout, ignores other hormonal effects of bariatric surgery and GLP-1 agonists, ignores hepatic glucose output, etc.
D. Increase sugar waste (SGLT-2-inhibitors do this, "safety valve" for high sugar levels)
You're saying the fundamental underlying driver is the amount of fat? But then you'd expect to see a correlation with amount of fat and insulin resistance, which is exactly what you don't see. People's insulin resistance drops way quicker than their weight.
Type of fat... I do believe if you consider the type of fat (trans, saturated vs. MUFA/PUFA), the lipolysis/lipogenesis confusion is less confusing, as inflammation feom lipotoxicity is actively being studied as a cause of insulin resistance.
I think coming back to the view of insulin resistance as an early symptom (preceded by hyperinsulineme but with normal glucose levels) of energy excess ties this all together. All this is from "from Obesity to Type 2 diabetes", details are probably wrong since its been a few yrs since I read it. This also ignores the role of the liver.
Basic logic is:
1. all humans (excepting those w/ rare diseases of fat cell differentiation) have a capacity for enegy buffering/storage because this is adaptive and a generally well-preserved trait in other animals.
2. in times of caloric excess, we increase fat deposition to store excess calories. This is mediated substantially through insulin. Biochemically, you'd see this with rising levels of insulin hormone production, with preserved/normal blood sugar levels.
3. Different people have differing capacities for insulin hormone production and different levels of fatness at which their capacity for energy storage becomes more resistant.
4. At this point, glucose levels start to rise, as insulin resistance rises and insulin hormone levels approach their max. This is prediabetes. At this point, these higher blood glucose levels are neccesary to keep driving calories into fat cells, even as those fat cells start to signal their full through insulin resistance.
5. At some point, your insulin levels can't rise further, and glucose levels reach "diabetic levels".
6. You have several therapeutic options.
A. Raise how much fat you can carry (thiazolidinediones do this)
B. Increase insulin production (exogenous insulin, sulfonyureas)
C. Reduce sugar intake (acarbose)
D. Reduce calorie intake (weight loss, GLP-1 agonists)
E. Reduce hepatic glucose output (Metformin)
From that perspective, it is easy easy to see why weight loss can so rapidly normalize symptoms. It is treating the fundamental underlying driver. Even mild weight loss can quickly move your equilibrium back to within-buffering range.
Further caveats: ignores pancreas burnout, ignores other hormonal effects of bariatric surgery and GLP-1 agonists, ignores hepatic glucose output, etc.
D. Increase sugar waste (SGLT-2-inhibitors do this, "safety valve" for high sugar levels)
You're saying the fundamental underlying driver is the amount of fat? But then you'd expect to see a correlation with amount of fat and insulin resistance, which is exactly what you don't see. People's insulin resistance drops way quicker than their weight.
It drops as soon as they enter negative energy balance, which fits with "exceeded personal energy buffering capacity"
Type of fat... I do believe if you consider the type of fat (trans, saturated vs. MUFA/PUFA), the lipolysis/lipogenesis confusion is less confusing, as inflammation feom lipotoxicity is actively being studied as a cause of insulin resistance.
Yeah, the inflammation argument wasn't convincing to me, as inflammation shouldn't resolve on fasting and then restart on a normal diet.