The discovery of insulin was a landmark in diabetes treatment. The rapidity that insulin transformed emaciated subjects from a state of near-death into relatively healthy figures demonstrating the obvious immediate benefit of insulin. Observations would initially be made about the short-term risks of insulin administration (e.g., hypoglycemia) of what was viewed simply as the replacement of a vital hormone. The risk of death from not using the life-saving therapy was rightfully seen as greater than any unknown risks associated with long-term insulin administration. Consequently, a paradigm shift occurred from a hepato-centric to a pancreato-centric theory of diabetes etiology. Initially, diabetes was treated as a single disease that would be treated with a single medication. However, observations of how diabetic patients responded to insulin could be generalized to phenotype would be made over the decade of its debut [1,2]. The pathophysiology of diabetes would be further worked out over time with scientific tools including radioimmunoassay (RIA) [3], euglycemic clamp (EC) [4], and immunofluorescence [5]. Administering exogenous insulin is known to cause a plethora of acute and chronic adverse effects. While inadequately discussed, negative long-term consequences of chronic hyperinsulinemia exist in diabetic patients. Iatrogenic insulin resistance (IIR) is one such inevitable outcome of the peripheral administration of exogenous insulin [6]. Hyperinsulinemia has been implicated in the development of cardiovascular disease (CVD) [7].

In current dogma, type 1 diabetes (T1D) is considered the insulin-dependent form, while type 2 diabetes (T2D) is the insulin-resistant form of diabetes. Shortly after a T1D patient begins administering exogenous insulin, the T1D patient also becomes insulin resistant. Effective care plans designed for T1D patients can only be formulated when considering the physiology behind IIR, which has accumulated evidence for its existence from well-respected and globally recognized researchers for more than six decades. The goal of this article is to promote understanding of this phenomenon so that clinicians might be better equipped to provide more effective therapeutic strategies for the care of diabetic patients.

Pancreato-centric Theory of Diabetes and the Era of Exogenous Insulin

Hepato-centric and pancreato-centric theories of diabetes etiology have been discussed for over a century [Figure 1]. Claude Bernard had been formulating a hepato-centric theory of diabetes from as early as the 1840s when he observed that the liver had higher concentrations of glucose than the portal system [8]. Bernard reported isolating glycogen in 1857. As he was exploring the role of the liver in the storage of sugar, he made many observations that led him to believe that diabetes was caused by either failure of hepatic glucose disappearance, hepatic glucose appearance, peripheral disappearance, or some combination of these factors [8]. Once Minkowski and von Mering showed that pancreatectomized dogs would develop diabetes in 1889, mainstream thinking regarding the etiology of diabetes began shifting from hepato-centric to pancreato-centric [8]. By January of 1922 the purified pancreatic extract that would become known as insulin was used on a young, emaciated patient with T1D [9,10]. Due to its success, diabetes clinics in the US and Canada began using this miracle drug to revitalize their diabetic patients. This led to a century of clinicians and researchers viewing diabetes purely as a disease of hormone deficiency despite accumulating evidence that this logic did not apply to a huge population of diabetic patients.

It only took about a decade after insulin first appeared for articles to be published documenting discrepancies in the quantity of insulin that was required to manage diabetes in two fundamentally differing phenotypes. Older, heavier patients oddly required much more while younger patients required much less insulin to improve sugar tolerance [1,2]. This was the first notion of difference in the quality of diabetes and would eventually be referred to as insulin dependent diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus (NIDDM).

Figure 1: Diabetes Concepts over Time.

By 1960, Yalow and Berson had published a landmark paper utilizing their RIA technique to quantify serum insulin [3]. The older, heavier diabetic subjects had more circulating insulin compared to the thinner, younger diabetic subjects. This is further evidence in support of the existence of two distinct types of diabetes. Autoimmunity gained notability as an important cause of IDDM in 1974 [5]. Bottazzo, a young fellow at Doniach’s Middlesex Hospital lab in London, used immunofluorescence of healthy type O blood donor pancreatic tissue mixed with sera of diabetic subjects [5]. Serum samples from diabetic subjects light up brightly, evidence of an autoimmune component.

What remained relatively static during these decades of diabetes research built upon novel techniques and understanding is the pancreato-centric model of diabetes. In the case of T1D, which is associated with β-cell loss, this model makes more sense. T2D pathology, at least initially, is driven by insulin resistance [11]. It would be prudent to reevaluate how we look at diabetes, considering the availability of more recent data since the advent of research tools such as RAI and EC.

Bihormonal Theory of Diabetes Revitalized the Role of the Liver in Diabetes

As discussed above, the hepato-centric theory predates the pancreato-centric theory of diabetes by several decades [8]. This mostly abandoned theory would regain vigor with accumulating evidence to support the notion that glucagon is a major player in the pathophysiology of diabetes. Glucagon antibodies were used in the development of RIA for glucagon by 1959 [12,13]. After developing a method to confidently measure glucagon [14], researchers were able to advance much of the understanding of the role of glucagon in diabetes pathology. Roger Unger described the problem of the relative hyperglucagonemia and insulin seen in both T1D and T2D when compared to healthy individuals as the “double-trouble hypothesis” [15]. The In the 1975 Banting Memorial Lecture, Unger reported that large quantities of insulin would be required to counteract the large influx of BG (caused by excessive glucagon) in order to achieve normoglycemia in diabetes [16].

Since 1959 the data to support the bihormonal theory of diabetes [16] have been overwhelming [17]. T1D, T2D, and latent-onset autoimmune diabetes of adults (LADA) result in a hyperglucagonemic state [18-20]. Glucagon increases the production of hepatic glucose and ketone bodies [21,22]. T1D patients presenting with diabetic ketoacidosis have double the normal levels of glucagon on admission, which is normalized by discharge [18]. Utilizing insulin lowers glucagon excretion, halting glucose and ketone body appearance in the liver.

Drugs that radically decrease serum glucagon such as Leptin and somatostatin return BG to normal or near normal levels in hyperglycemia secondary to insulin deficiency [23,24]. There are animal model studies suggesting glucagon is a major contributor to hyperglycemia. In glucagon receptor knockout mice that do not develop diabetes even after the destruction of the pancreatic β-cells [25, Figure 3]. Glucagon receptor antibodies maintained normoglycemia in T1D mice [26, Figure 4]. Marked elevation in serum glucagon results when healthy pancreata are perfused with antibodies targeting insulin [27]. Current FDA-approved insulin therapy modalities are likely to worsen the hyperglucagonemia seen in both T1D and T2D patients, which is discussed below.

Figure 2: Glucagon Receptor (GCGR) KO Mice.

Figure 3: Glucagon Antibodies in Mice.

Iatrogenic Insulin Resistance (IIR)

Researchers in 1961 determined that about half of the insulin secreted by the pancreas would be extracted by the liver [28-30]. Yalow observed in 1965 that exogenously administered insulin would result in a higher concentration of serum insulin than when insulin was secreted endogenously [31]. Yalow then suggested that hepatic glucose regulation was influenced by hepatic insulin extraction. Details regarding these findings were worked out over the next few decades. In 1979 DeFronzo and colleagues developed the gold standard of insulin resistance measurement, known as the EC [32]. DeFronzo first published findings of insulin resistance in T1D subjects in 1982 [33] the same finding was repeated over numerous studies. In 2015 a meta-analysis found that 38 out of 38 EC studies reported IR in T1D subjects [34].

When compared to portal delivery, systemic delivery of insulin induces IR in both healthy and diabetic subjects. Twelve T1D subjects were administered insulin via intraportal or continuous subcutaneous insulin infusion for 4 months. The intraportal group had quicker improvements in glycemic control with less insulin than the continuous subcutaneous group [35]. Hemoglobin A1c (HbA1c) improved much more in the portal delivery group (13.9% to 5.5%) than the systemic delivery group (14.8% to 10%) despite less insulin being administered to the portal delivery group. Subjects (N=16) status post kidney-pancreas transplant only became insulin resistant (measured via EC) if the circulation was routed into the systemic circulation [36]. In addition, the amount of insulin required to lower free fatty acids by 50% was double in the systemic circulation group.

The overall physiological mechanism of IIR can be seen below [Figure 4]. Islets are interspersed throughout the pancreas. The predominant islet cell is the β-cell, which is responsible for the production of insulin, amylin, and likely other compounds not yet discovered. Other cells such as α- and δ-cells are intermixed in the islets, primarily in the outer portion known as the mantle, that produce glucagon and somatostatin, respectively. The hormones mentioned here exert both paracrine and endocrine effects. Peripheral administration of any of the hormones will bypass any paracrine effect within the islets as well as any proximal endocrine effects in the portal system and liver.

High concentrations of insulin are required to both increase glucose disappearance and suppress glucose appearance in the liver. The liver extracts approximately 40 to 80% of the insulin from the portal system [37] in order to regulate BG in a homeostatic manner. The ratio of the serum portal to systemic insulin is approximately 3.0 in healthy subjects, while the ratio is decreased to 0.8 in subjects after systemic delivery of insulin [38]. Any decrease in portal concentration of insulin will cause a subsequent increase in peripheral BG due to homeostatic dysregulation. Increases in BG peripherally lead to increased systemic insulin requirements to achieve normal BG. Higher systemic insulin concentration over time (e.g. chronic hyperinsulinemia) leads to IR of peripheral (e.g. adipose and muscle) tissue [39]. It is likely that the etiology of IIR is multifactorial with some contribution from chronic hyperglycemia. Older data suggest this is the case, but more recent data suggest hyperinsulinemia drives IIR [40]. With current treatment options it might not matter as matching large quantities of carbohydrates with large quantities of insulin inevitably results in both hyperglycemia and hyperinsulinemia, which will be discussed below.

Glucagon has an opposing effect on hepatic glucose regulation when compared to insulin. Normal physiological suppression of glucagon release by α-cells via paracrine mechanism does not occur when insulin is peripherally administered [21]. In addition to directly inhibiting α-cell glucagon release, insulin indirectly inhibits it by stimulating somatostatin release by δ-cells. It is debated whether paracrine effect or proximal endocrine effect of physiological insulin secretion primarily drives IIR [41,42]. However, this topic is beyond the scope of this article, and it should be noted that exogenous insulin administration clearly bypasses both the paracrine and proximal endocrine effects of endogenous insulin secretion.

Figure 4: Physiologic Versus Peripheral Insulin Delivery.

Physiologic: Insulin is in its highest concentration in proximity to the islet cells at around 2,000 μU/mL. High concentrations are required to exert a paracrine effect on the α-cells, which causes a drop in glucagon release. As the portal vein delivers insulin to the liver insulin is diluted to about 60 μU/m. The liver then extracts 40-80% of the insulin. Insulin is then further diluted from other blood supplies.

Peripheral: Insulin enters the circulation from the periphery, bypassing the pancreas and liver. Excessive glucagon is produced in the α-cells of the pancreas (T2D), gastric fundus (T1D and T2D), and small bowel (T1D and T2D).

Hepato-selective Therapies

While hyperinsulinemia is seen in obesity, only IR obese subjects have impaired insulin clearance when compared to obese insulin-sensitive subjects [43]. IIR results from bypassing the liver where normally approximately half of the insulin is extracted. The commonality is that both the IR that would lead to metabolic syndrome (MetS) [43] and the IR seen in PID involves inadequate hepatic regulation of glucose. Thus, hepato-selective therapies could be beneficial in both T1D and T2D [Table 1].

The issue of hyperglucagonemia and IIR has led to the development of drugs that target the liver. Somatostatin showed marked reductions in hyperglycemia and glycosuria as early as 1978 [44], however, side effects have limited its long-term use. Similar improvements in glycemic control were seen in T1D subjects restricting carbohydrate content to 30 grams daily when glucose absorption was minimal [44].

Amylin is a hormone that is co-secreted with insulin that decreases appetite, slows nutrient absorption, and suppresses glucagon release from the α-cells. Pramlintide is an analog of amylin that reduces insulin requirements, promotes weight loss, and provides improved glycemic control when added to insulin therapy [45]. Barriers to use include the unwillingness of the patients to inject an additional medication and the increased complexity of the drug regimen.

Some medications can improve insulin requirement and metabolic syndrome, such as metformin in T1D subjects [46], although data are limited regarding long-term effects. The SGLT-2i drug class has been shown to lower insulin requirements, however, is not FDA-approved for use in T1D. Several small studies of the DPP-4i drug class suggest the class may lower insulin requirements as well as β-cell preservation in LADA [47-52]. A metanalysis shows similar results for T1D subjects using DDP-4i drugs [53].

Therapies specifically targeting the liver are under work. Glucagon receptor antagonists have been shown to increase weight, LDL, and liver transaminases in T2D subjects [54,55]. Hepato-selective glucokinase activators could provide some benefits but are early in development. Oral insulin delivery has been considered as it passes through the portal system after absorption. However, utility is questionable due to limited bioavailability [40], which is affected by food in the gut [56]. Intraperitoneal or intraportal insulin delivery would be a viable solution if the catheter required to administer the insulin was not invasive and did not increase the risk of infection [57,58].

Eli Lily developed a hepato-preferential basal insulin called peglispro that preferentially targeted hepatocytes. By phase 3 clinical trials when it became evident that while peglispro had decreased weight, insulin requirements, and hypoglycemic events in subjects taking it versus insulin glargine, it seemed to be contributing to fatty liver [59]. This could be attributable to peglispro’s high affinity to hepatic tissue and low affinity to adipose tissue. Inadequately stimulated adipocytes would liberate triglycerides while overstimulated hepatocytes would uptake those triglycerides. Due to concerns of the cost associated with testing to explain these findings, Eli Lily decided to abandon the novel basal insulin [59]. This is disappointing because a hepato-preferential insulin such as peglispro could theoretically be mixed with an existing FDA-approved basal insulin at a ratio that would better mimic the normal physiological portal to systemic circulation insulin ratio.

Table 1: Therapies that Target the Liver or Lessen Insulin Requirements.

Peripheral Insulin Delivery (PID) Contributes to Hypoglycemic Episodes

PID increases the risk of hypoglycemia due to multiple mechanisms. T1D patients have blunted stress hormone responses to hypoglycemia, particularly if there has been a hypoglycemic episode in the prior 24 hours [60-62]. PID does not suppress hepatic glucose appearance, which can cause an increasing demand for inadequate stress hormones and increase IIR over time. Glucose variability and hypoglycemic episodes result from this pattern in T1D patients on HCD regimens [63].

The Law of Small Numbers to Reduce Hypoglycemic Episodes

Dr. Richard K. Bernstein is an engineer turned diabetologist. He was diagnosed with T1D as a child and was treated with the standard method for 2 decades until he acquired an Ames Reflectance Meter [Figure 5] in the late 1960s [10]. After inventing self-blood glucose monitoring (SBGM) and utilizing the only diet that would allow him to achieve normal blood glucose (BG), an LCD, he reached out to the American Diabetes Association (ADA) to share his remarkable results. The ADA ignored him, so he went to medical school at age 45 and eventually completed an Endocrinology fellowship. It took more than 2 decades and the results from the DCCT before the ADA would even recognize that SBGM might be beneficial to T1D patients.

Figure 5: Original Ames Reflectance Meter (1969).

A mathematical concept known as the Law of Small Numbers (tLSM) was suggested by Bernstein [64]. This is a mathematical truth that is also intuitively true. The larger the amount of substrate that is introduced into a system, the larger the effect of that substrate will be. For insulin, this means that the more insulin needed to cover higher BG, the greater the risk for either hypo- or hyperglycemia. The FDA, for example, requires food manufacturers to only be within a 20% margin of error for the energy and macronutrient content of the food product to comply with their requirements [65]. Unprocessed foods rich in carbohydrates have variations among crops, species of the same produce, preparation practices, etc., that make estimating the carbohydrate content inaccurate. Because of fear of hypoglycemia, normal blood sugars cannot be obtained when consuming a large amount of carbohydrates. The most obvious approach to address tLSM is to prescribe an LCD diet. While tLSM was suggested before continuous glucose monitoring was widely available, it is now easier than ever for patients and clinicians to measure the effects of dietary modification on interstitial glucose in real time [66-70]. Data gathered from an online community utilizing Dr. Bernstein’s method showed superior glycemic control with fewer episodes of hypoglycemia [71]. However, rigorous data are needed to test the impact of an LCD on T1D patients.

Low Carbohydrate Diets (LCD) Precede Low Fat Diets as the Diabetes Medical Nutrition Therapy (MNT)

Recorded use of LCD began in 1777 when John Rollo treated his first diabetic patient with his animal diet [10]. The first case Rollo saw provided little information as the patient was soon discharged. The second case he saw in 1796 was deemed a success as the patient effectively put his diabetes into remission and lived almost 13 years longer in seemingly good health after implementing the animal diet. After producing a pamphlet containing these case reports and his hypothesis asking for anecdotes of others that tried the animal diet. Rollo then published findings from two dozen physician respondents, alongside his 2 cases, into a book. Thereafter, variations of the LCD would be used for the treatment of diabetes for over a century in countries throughout Europe. The LCD was recommended by William Osler as the standard of care for diabetes treatment in North America [72].

The starvation diet was popularized in 1915 after experiments performed by Allen suggested that pancreatectomized dogs would live longer if semi-starved. Allen and Joslin tried the same thing on emaciated diabetic patients, which also seemed to live longer assuming the patients did not die of inanition first. Randomized controlled clinical trials did not exist at the time so there was no formal testing to suggest otherwise. Observations of the long-term effects were likewise made as time went on. Cardiovascular disease (CVD), for example, seemed to be one of the more serious long-term sequelae of replacing insulin. Proponents of the LCD in that era, namely Newburg and Marsh, were late to the scene and published their findings treating diabetic patients with a high-fat, LCD [73] after public opinion had been shifted toward the starvation diet. Joslin was gaining credibility through the use of insulin as he became the most prominent diabetologist of the era and popular opinions would largely be influenced by him for decades [10]. Cardiologists would soon begin to recommend low-fat diets for the prevention of CVD, which would be copied and pasted into the management of the pathology of almost every pathology over time, including diabetes. Joslin furthered his suspicion that the high-fat LCD that was standard-of-care for diabetic patients prior to the discovery of insulin was to blame as the blood of diabetic patients frequently appeared milky [10]. However, many forms of the LCD are making a comeback as a possible diabetes medical nutrition therapy (MNT). The ADA reversed its recommendation to avoid LCDs in the 2019 Standards of Medical Care in Diabetes with the following statement: “research indicates that low-carbohydrate eating plans may result in improved glycemia and have the potential to reduce antihyperglycemic medications for individuals with type 2 diabetes” [74].

Problems Caused by Insulin Resistance

MetS is caused by IR and is associated with a greater risk of CVD [11]. This is the traditional notion of IR that is attributed to T2D and its associated sequelae. Both T1D (if treated with PID) and T2D are characterized by a state of IR and hyperinsulinemia. Both types of diabetes share similar sequelae, much of which would result from either the states of IR, hyperinsulinemia, or both. In T1D patients, chronic hyperglycemia causes many microvascular complications including retinopathy, peripheral neuropathy, and nephropathy [75,76] while evidence suggests that macrovascular sequelae such as CVD are more associated with hyperinsulinemia [7]. Additionally, data suggest that good glycemic control measured by HbA1c in T1D patients does not provide any benefit in reducing CVD risk [75,77]. While most of the research regarding cancer risk in diabetic patients has been done in T2D, there is considerable data implicating insulin as a contributor to the etiology of cancer. Cancer-related mortality is increased in T2D patients that use PID or sulfonylureas [78]. Risk of malignancies such as liver, pancreatic, breast, colon, and endometrial cancers is increased in diabetes [79,80].

The relative risk of developing dementia was markedly increased in 1,077 T1D patients (118–314%) in a population-based cohort study based on Taiwan National Health Insurance Claims [81]. The relative risk of developing dementia is profoundly increased in T1D when compared to that reported 32,320 T2D patients (15-28%) [81]. A 2016 meta-analysis suggested a stronger correlation between T2D and dementia (60%), and an increased risk of vascular dementia in women [82]. Alzheimer’s disease risk is roughly doubled in individuals with hyperinsulinemia and is even higher in those without a diagnosis of diabetes [83]. A systematic review suggests associations between dementia and diabetes based on pathophysiology related to atherosclerosis, microvascular disease, glucose toxicity, and insulin. [84].

The clinical outcomes mentioned above can be explained by biochemical processes. Chronic hyperglycemia (e.g., glucose toxicity) increases reactive oxygen species (ROS) which causes impaired β-cell function and IR, which leads to worsening glucose tolerance [85]. ROS generation is multifold and will be briefly and incompletely mentioned here as it is beyond the scope of this article. The non-enzymatic production of advanced glycosylation end products (AGEs), influenced by the concentration of sugar molecules such as glucose and fructose, results in increased ROS [86]. Fructose glycosylates protein at a rate of 7.5 to 10 times that of glucose [86]. Sucrose is a disaccharide that is roughly 50:50 glucose to fructose in composition and makes up >15% of the energy intake of approximately 30% of the US population [87]. Thus, limiting added sugars would be beneficial in reducing the biochemical processes associated with diabetes. β-hydroxybutyrate (β-HB) is a byproduct of fat metabolism that can elevate during LCDs and fasting. β-HB decreases ROS by functioning as an antioxidant for the hydroxyl radical and inhibiting mitochondrial ROS production via increasing the NAD+/NADPH ratio, and other mechanisms [88]. Placental production of β-HB, particularly in the second trimester, provides an important source of energy for the developing human fetus [89]. LCDs are effective at weight and BG control in overweight or diabetic expectant mothers, respectively [89].

Thus, by decreasing serum insulin area under the curve, lowering the production of ROS, increasing removal of ROS, increasing β-HB, and other positive effects, LCDs would be beneficial in improving upstream multiple factors responsible for diabetic-related sequelae that appear downstream.

Both the use of LCD as an MNT for diabetes therapy and the hepato-centric theory of the etiology of diabetes predate low-fat high carbohydrate diets and the pancreato-centric theory of diabetes, respectively. The discovery of insulin shifted the paradigm. However, the liver is an important participant in the pathophysiology of both T1D and T2D that is inappropriately ignored in diabetic treatment. Failure to suppress glucose appearance and stimulate glucose disappearance at the level of the liver contributes to BG surges both while fasting and after meals in all forms of diabetes. T2D has long since been described as a condition caused by IR, while the etiology of T1D is frequently attributed to a lack of the essential hormone insulin. PID leads to IIR, which contributes to the increasing need for PID. This vicious cycle may be inevitable to some degree, but a proper understanding of the physiology behind it is necessary to formulate adjunctive medical and lifestyle interventions to mitigate IIR. Hepato-preferential medications are still lacking. LCD will lower the risk of both hypoglycemia and hyperglycemia mathematically via tLSM, reduce hyperinsulinemia, lower the risk of IIR, and improve the typical biochemical environment associated with diabetes. Continuous glucose monitoring gives patients instant data to see how they will respond to certain foods to guide and motivate appropriate eating behaviors.

Conflict of interest

The authors declare no conflict of interest.

Funding

There was no funding received for this paper.

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