Insulin levels change before weight loss or obesity

High insulin levels, provoked by spikes in blood glucose due to high glycemic foods or stress chemistry, block the metabolism of calories for energy and force them to be stored as visceral fat.

A recent study published in JAMA Network Open helps to dispel the mistaken assumption that obesity precedes insulin resistance.

The authors posed the question:

“What are the temporal associations among higher body mass index (BMI) and chronic inflammation and/or hyperinsulinemia?”

To answer this, they conducted a meta-analysis of 60 eligible studies whose data points included BMI, fasting insulin, and CRP (C-reactive protein, a biomarker for inflammation).

Changes in fasting insulin precede changes in weight

The authors note about the various adverse health outcomes associated with obesity and how the causal direction has been mistaken:

“The putative links between obesity and adverse outcomes are often attributed to 2 potential mediators: chronic inflammation and hyperinsulinemia. These characteristics have been associated with several NCDs [non-communicable diseases], including obesity as well as type 2 diabetes, cardiovascular disease,17 and chronic kidney disease.18 Existing data on the association of obesity with chronic inflammation and/or hyperinsulinemia are chiefly cross-sectional, making it difficult to confirm the direction of any causality. This systematic review and meta-analysis summarizes evidence on the temporality of the association between higher BMI and chronic inflammation and/or hyperinsulinemia. We hypothesized that changes in chronic inflammation and hyperinsulinemia would precede changes in higher BMI.”

Their data show that improvement in fasting insulin occurring before weight loss is the dominant factor:

“This systematic review and meta-analysis suggests that decreases in fasting insulin are more likely to precede decreasing weight than are decreases in weight to precede decreasing levels in fasting insulin. After accounting for the association between preceding levels of fasting insulin and the subsequent likelihood of weight gain, there was no evidence that inflammation preceded subsequent weight gain... This temporal sequencing (in which changes in fasting insulin precede changes in weight) is not consistent with the [mistaken] assertion that obesity causes NCDs and premature death by increasing levels of fasting insulin.”

This is not the first time that the correct causal relationship has been observed:

Medications that increase insulin levels

Exogenous insulin (injection) and medications that increase insulin levels (sulfonylureas and meglitinides), and the effects of bariatric surgery, show the same relationship.

“In patients with type 2 diabetes, RCTs have found that introducing exogenous insulin and sulfonylureas (which increase endogenous insulin production) compared with lower doses or no drug therapy produce increases in weight.85,86 Some patients with type 1 diabetes deliberately omit or reduce their insulin injections to lose weight.87 Similarly, reports after bariatric surgery consistently indicate that insulin levels decrease before weight decreases in patients undergoing bariatric surgery.88 Thus, the finding that changes in insulin levels tend to precede changes in weight rather than the other way around has been previously demonstrated in 3 different scenarios. To our knowledge, there is no clinical evidence demonstrating that weight gain or loss precedes increases or decreases in endogenous insulin.”

As for liposuction, this implies that such weight loss without the changes in insulin does not protect from adverse health outcomes:

“Insulin resistance, a cause and consequence of hyperinsulinemia,89 leads to type 2 diabetes and is associated with other adverse outcomes, such as myocardial infarction, chronic pulmonary disease, and some cancers,90,91 and may also be indicated in diabetic nephropathy.92 Despite the 3 scenarios described earlier, it is commonly believed that obesity leads to hyperinsulinemia.93-95 If the converse is true and hyperinsulinemia actually leads to obesity and its putative adverse consequences, then weight loss without concomitant decreases in insulin (eg, liposuction) would not be expected to address these adverse consequences.

Public health implications

In their conclusion, the authors state:

“The pooled evidence from this meta-analysis suggests that decreases in fasting insulin levels precede weight loss; it does not suggest that weight loss precedes decreases in fasting insulin. This temporal sequencing is not consistent with the assertion that obesity causes NCDs and premature death by increasing levels of fasting insulin. This finding, together with the obesity paradox, suggests that hyperinsulinemia or another proximate factor may cause the adverse consequences currently attributed to obesity.”

This implies that the target for diets, medications, and therapies should not be the number on the scale but the levels of insulin and sensitivity versus resistance to insulin of the whole body.

Fructose and sucrose spur fat production

An example of how insulin drives fat production is offered by a study recently published in the Journal of Hepatology demonstrating that fructose and sucrose increase hepatic lipogenesis (fat production in the liver) and promote long-term metabolic dysfunction.

The authors set out to determine if fructose alone or fructose-glucose (sucrose) would drive fat production independent of excessive caloric intake.

“Excessive energy intake from free sugars, and in particular from increased fructose intake, is associated with obesity, metabolic syndrome and NAFLD. [3],[4] Moreover, evidence exists that high-fructose intake increases hepatic de novo lipogenesis and hepatic fat content and decreases hepatic insulin sensitivity independently from weight gain. [5] Even consumption of sugar-sweetened beverages (SSBs) containing moderate amounts of fructose for a few weeks changes the serum fatty acid (FA) profile and induces hepatic insulin resistance. [6],[7]”

So they investigated the metabolic effects of moderate fructose, sucrose and glucose intake – in a liquid form as sugar-sweetened beverages (SSBs) with a 6-week intervention of SSBs containing moderate amounts (80 g/day) of free fructose, fructose in combination with glucose (sucrose), glucose, or SSB abstinence, and compared the impact on liver fat synthesis.

Regular consumption of both fructose- and sucrose-sweetened beverages in moderate doses – even when associated with stable caloric intake -

– increases hepatic FA synthesis even in a basal state; this effect is not observed after glucose consumption.

In addition, the authors found adverse effects for cardiovascular health:

This study confirmed that consumption of fructose-containing SSBs changes LDL composition as described previously. [48] In the intervention group with added sucrose, there was a significant change of the LDL particle distribution towards smaller, more atherogenic particles associated with cardiovascular disease. [49]

The also note impairments of free fatty acid (FFA) metabolism by muscles:

Replacement of lipid energy substrate in the skeletal muscle by metabolites generated from fructose, i.e. lactate or glucose, may spare lipids from oxidation and increase intramuscular fat content, which is supposed to decrease muscular FFA uptake and oxidation. [43], [44] Decreased FFA utilization by the skeletal muscle is supposed to increase FFA flux to the liver, which could – in combination with impaired hepatic FA oxidation due to regular fructose consumption – promote hepatic fat deposition and insulin resistance. [16], [43]

Modest amounts of sugar increase persistent fat synthesis

In an interview by Technology Networks Proteomics and Metabolomics, the authors state:

“Eighty grams of sugar daily, which is equivalent to about 0,8 liters of a normal soft drink, boosts fat production in the liver…”

…And the overactive fat production continues for a longer period of time, even if no more sugar is consumed,” says study leader Philipp Gerber of the Department of Endocrinology, Diabetology and Clinical Nutrition.”

“The body’s own fat production in the liver was twice as high in the fructose group as in the glucose group or the control group – and this was still the case more than twelve hours after the last meal or sugar consumption,” says Gerber. Particularly surprising was that the sugar we most commonly consume, sucrose, boosted fat synthesis slightly more than the same amount of fructose…Increased fat production in the liver is a significant first step in the development of common diseases such as fatty liver and type-2 diabetes.”

This has significance beyond the parameters of this study according to the study authors…

To our knowledge, this is the first study to apply tracer-based methodology to quantify metabolic changes induced by interventional SSBs (with moderate fructose, sucrose or glucose content) alongside the habitual diet. Thus, this study provides findings that are highly relevant to everyday life. The finding that regular consumption of fructose-containing beverages increases hepatic basal lipogenic activity is in accordance with mechanistic animal studies that showed that fructose and sucrose are more potent inducers of lipogenic gene expression than glucose. [10]

It’s the insulin

In a perspective published in Medscape Family Medicine, former editor-in-chief of JAMA George Lundberg, MD writes:

“…huge numbers of humans are destined to fatten unless their insulin levels are kept very low. The drive to lower fat and cholesterol from 1980 turned the switch that opened the floodgates of obesity. What we now recognize as a public health debacle led to the new, mostly unrecognized, plague of elevated blood insulin.”