Hypothesis: Insulin exposure causes insulin resistance

richard · 2017-02-13 11:40:42 UTC

So I want to collect studies that support (or refute) common hypotheses. We’ll start with this idea - that chronic exposure to high levels of insulin causes insulin resistance, and it’s corollary that exposure to lower levels decreases it.

richard · 2017-02-13 12:09:46 UTC

This study implanted micro pumps into rats that gave the rats extra insulin (controls got saline). After 10 days the insulin levels were naturally higher, the glucose levels however were not lower … indicating the rats had become insulin resistant.

ncbi.nlm.nih.gov

Exogenous hyperinsulinemia causes insulin resistance, hyperendothelinemia, and subsequent hypertension in rats.

CC Juan, VS Fang, CF Kwok, JC Perng, YC Chou and LT Ho, Metabolism: clinical and experimental, Apr 1999

In many clinical and animal studies, hypertension and insulin resistance coexist, but their mechanistic relationship is unclear. We explored the causal link between these two parameters in a rat model with chronic hyperinsulinemia induced with human insulin (1 U/d) released from subcutaneously implanted minipumps. Rats with saline minipumps served as a control. During the first experiment, plasma levels of insulin and glucose and the systolic blood pressure of the two groups were continuously monitored for 17 days. In the subsequent four experiments, rats were killed on days 10 and 13 to measure plasma endothelin-1 (ET-1) levels and the glucose transport into and insulin and ET-1 binding of isolated adipocytes. In one experiment, rats were tested for oral glucose tolerance on days 10 and 13. In another experiment, ET-1 binding to the aortic plasma membrane was also determined. The results showed that rats became hyperinsulinemic throughout the experimental period by the instillation of exogenous insulin. Hyperinsulinemic rats were consistently hypoglycemic during the first day, but they became euglycemic thereafter, indicating an insulin-resistant state. Glucose intolerance was obvious by day 10, but significant hypertension was not detected until the 11th day on insulin infusion. Compared with the saline controls, insulin-infused rats had an increase of plasma ET-1 levels but a decrease of both basal and insulin-stimulated glucose transport into adipocytes. ET-1 binding to adipocytes of the insulin-infused group was elevated significantly from day 10 through day 13. ET-1 binding to the aortic membranes, supposedly downregulated by the increased plasma ET-1 and hypertension, was similar to that found in the controls on day 13. These results imply that hyperinsulinemia in rats could lead to hypertension via the elevation of plasma ET-1 levels together with an unaltered vascular binding of ET-1, which was probably unrelated to the insulin resistance.

from the study

Despite the persistent hyperinsulinemia originating from the insulin minipump, the rats maintained euglycemia after day 2 of the experiment (Fig 1). One could suspect that these rats may have a nullified blood glucose-lowering effect of hyperinsulinemia by mobilization of glucose-counterregulatory factors, including glucagon. However, based on our results, we believe these hyperinsulinemic rats developed insulin resistance very quickly.

richard · 2017-02-13 12:25:05 UTC

This study exposed insulin resistant people to a chemical that inhibits insulin secretion (diazoxide) for 8 weeks and saw greater weight loss (than the placebo control) greater decrease in body fat and increase in fat free mass and less insulin in response to glucose (as you would expect) … yet no increase in glucose (per an intravenous glucose tolerance test).

ncbi.nlm.nih.gov

Beneficial effect of diazoxide in obese hyperinsulinemic adults.

R Alemzadeh, G Langley, L Upchurch, P Smith and AE Slonim, The Journal of clinical endocrinology and metabolism, Jun 1998

Hyperinsulinemia, insulin resistance, and increased adipose tissue are hallmarks of the obesity state in both humans and experimental animals. The role of hyperinsulinemia as a possible preceding event in the development of obesity has been proposed. We previously demonstrated that administration of diazoxide (DZ), an inhibitor of insulin secretion, to obese hyperinsulinemic Zucker rats resulted in less weight gain, enhanced insulin sensitivity, and improved glucose tolerance. Assuming that hyperinsulinemia plays a major role in the development of human obesity, then its reversal should have therapeutic potential. To test this hypothesis, we conducted a randomized placebo-controlled trial in 24 hyperinsulinemic adults [body mass index (BMI) > 30 kg/m2]. All subjects were placed on a low-calorie (1260 for females and 1570 for males) Optifast (Sandoz, Minneapolis, MN) diet. After an initial 1-week lead-in period, 12 subjects (mean +/- SE for age and BMI, 31 +/- 1 and 40 +/- 2, respectively) received DZ (2 mg/kg BW.day; maximum, 200 mg/day, divided into 3 doses) for 8 weeks; and 12 subjects (mean +/- SE for age an BMI, 28 +/- 1 and 43 +/- 1, respectively) received placebo. Compared with the placebo group, DZ subjects had greater weight loss (9.5 +/- 0.69% vs. 4.6 +/- 0.61%, P < 0.001), greater decrease in body fat (P < 0.01), greater increase in fat-free mass to body fat ratio (P < 0.01), and greater attenuation of acute insulin response to glucose (P < 0.01). However, there was no significant difference in insulin sensitivity and glucose effectiveness, as determined by the insulin-modified i.v. glucose tolerance test (Bergman's minimal model) and no significant difference in glycohemoglobin values.8 weeks treatment with DZ had a significant antiobesity effect in hyperinsulinemic obese adults without inducing hyperglycemia.

This study does show that reducing insulin lowers body fat, but it also shows that people in the treatment arm were able to maintain glucose control with less insulin - effectively making them more insulin sensitive…

carolT · 2017-07-29 18:10:06 UTC

Yes, insulin receptors do run away and hide.

Continuous exposure to insulin causes a reduction in the number of receptors exposed on the cell surface by promoting internalization as well as degradation of hormone-occupied receptors (6). The insulin receptor is a tyrosine kinase that activates itself and then transmits its stimulatory message by promoting the phosphorylation of selected tyrosines on the receptor and on postreceptor partner molecules such as insulin receptor substrate family members IRS-1 and IRS-2 in the family of insulin receptor substrates. With continuous exposure to insulin, the receptor’s kinase activity is diminished, probably because of combined effects of phosphorylation of serine residues on the receptor, dephosphorylation of tyrosines by the action of phosphatases, and the binding of inhibitory molecules (41–45)

Many other references in full paper. Full title: “Insulin Resistance and Hyperinsulinemia Is hyperinsulinemia the cart or the horse?”

Darcy · 2017-09-20 20:06:03 UTC

Do you know if Diazoxide is being used as a weight loss or diabetes medication? It sounds like it might have potential. This vicious cycle of insulin-makes-you-fat and obesity-makes-you-have-higher-insulin is enough to drive one crazy.

A the beginning of this podcast, you mentioned an insulin greater than 14 prevents weight loss. Do you have any links to share with more information on that?

I am wondering if anyone has done tests on insulin levels during an extended fast. How long does it take for insulin to reduce, and is the timeframe of that related to how high the person’s A1C is, and how insulin resistant they are?

I have so many questions, coming from frustration, about how long it will take to get permanent effects (especially reversal of diabetes and weight loss) from fasting/insulin lowering. If it were possible to get insulin tested daily during a 5-day fast, for instance, would that be worth doing, just to verify insulin does go down with fasting and to see how long it takes to get below 14?

I really wish someone could come up with that much sought-after home insulin test!

richard · 2017-09-20 22:01:44 UTC

The study that identified insulin inhibition of lipolysis was https://www.ncbi.nlm.nih.gov/pubmed/2573554

They charted the difference between lipolysis inhibition for insulin dependent diabetics and non-diabetics … I assume that obese people with insulin resistant adipose tissue (but not specifically insulin dependent) have a similar curve to the insulin dependent diabetcs as they have both high insulin and overflow of NEFA.

INsulinLipolysis

The important thing is for people who have insulin sensitive adipose it doesn’t take much insulin to completely inhibit the release of energy from body fat. I mapped pMol/l to mIU/L (top X axis)