Unmet needs in the treatment of type 1 diabetes: why is it so difficult to achieve an improvement in metabolic control?

Abstract

The development of advanced diabetes technology has permitted persons with type 1 diabetes mellitus to improve metabolic control significantly, particularly with the development of advanced hybrid closed-loop systems which have improved the quality of life by reducing hypoglycemia, decreasing macroangiopathy and microangiopathy-related complications, ameliorating HbA1c and improving glycemic variability. Despite the progression made over the past few decades, there is still significant margin for improvement to be made in terms of attaining appropriate metabolic control. Various factors are responsible for poor glycemic control including inappropriate carbohydrate counting, repeated bouts of hypoglycemia, hypoglycemia unawareness, cutaneous manifestations due to localized insulin use and prolonged use of diabetes technology, psychosocial comorbidities such as eating disorders or ‘diabulimia’, the coexistence of insulin resistance among people with type 1 diabetes and the inability to mirror physiological endogenous pancreatic insulin secretion appropriately. Hence, the aim of this review is to highlight and overcome the barriers in attaining appropriate metabolic control among people with type 1 diabetes by driving research into adjunctive treatment for coexistent insulin resistance and developing new advanced diabetic technologies to preserve β cell function and mirror as much as possible endogenous pancreatic functions.

Introduction

Type 1 diabetes mellitus (T1D) is an autoimmune disease characterized by pancreatic β cells destruction, resulting in absolute insulin secretion deficit with consequent hyperglycemia [1]. For decades, the gold-standard treatment of T1D was multiple daily injections, however, the development of new diabetes technologies such as continuous glucose monitoring (CGM) and continuous subcutaneous insulin infusion, which attempt to mirror endogenous pancreatic insulin secretion in a more physiological manner, has led to a significant amelioration in glycated hemoglobin (HbA1c) and hence are being more widely implemented in clinical practice. In T1D, CGM systems are associated with 0.5–1% reduction in HbA1c without increased risk of hypoglycemia [2]. Many studies have demonstrated a significant decrease in hypoglycemia and microangiopathy and macroangiopathy-related complications with the use of new technologies [3]. However, despite such improvements, about 12–14% of people with T1D still display frankly elevated HbA1c, over 75 mmol/mol or 9% [3].

The development of CGM systems allows physicians to utilize new parameters which provide useful information regarding intra-and inter-day glucose variations [4]. The introduction of advanced hybrid closed loop (AHCL) systems has permitted an even better improvement of metabolic control compared to the use of CGM and continuous subcutaneous insulin infusion as separate components, with most studies suggesting a 10% increase in Time in Range (TIR) over a 12-month period [5].

Despite the significant improvement in metabolic control, there is still considerable opportunity for improvement in terms of metabolic control and quality of life among people with T1D. This is highlighted in the recently published T1D Exchange data that demonstrated only 21% of adults and 17% of youth achieve desired HbA1c targets [6]. Several factors can interfere with the achievement of appropriate metabolic control including incorrect carbohydrate counting [7], hypoglycemia unawareness [8], skin complications [9] and ‘diabulimia’ [10].

A relatively new concept is that of ‘Double Diabetes’ which refers to people with T1D which also have insulin resistance and constitutes an important barrier in achieving appropriate metabolic control. The increased incidence of overweight and overt obesity among people with T1D has increased the prevalence of this phenomenon. The addition of adjunctive medications used in the treatment of type 2 diabetes (T2D) to intensive insulin therapy in the management of T1D may lead to improved insulin sensitivity, improve HbA1c, decrease total daily insulin dose and ameliorate glycemic control.

Perhaps, the most important hurdle to overcome for attaining metabolic control is the inability to mirror endogenous pancreatic insulin secretion. Exogenously administered insulin does not follow the oscillatory portal-vein hepatic insulin delivery seen in the endogenous pancreas [11]. New research in diabetes technology is attempting to surmount this barrier, and mimic endogenous pancreatic insulin delivery through the development of new algorithms and dual-hormone pumps containing glucagon. Indeed, the purpose of this review is to comprehensively understand and overcome the barriers in achieving appropriate glycemic control with a particular focus on the role of adjunctive therapies and novel diabetes technology, with the hope to drive research to further improve metabolic control and improve patient quality of life by preserving β cell function.

Concept of metabolic control and glycemic variability

Glycated hemoglobin

HbA1c remains the current gold standard for the assessment of glycemic control in people affected by diabetes mellitus and can be used as a marker for glycemic control in the last 3–4 months. Therefore, the measurement of HbA1c correlates with metabolic control, where altered values indicating high glycemic fluctuations which correlate with complications including hypoglycemia, macroangiopathies and microangiopathies [12].

Despite HbA1c remaining the gold standard marker for metabolic control in people with diabetes, there are many conditions which may alter the HbA1c reading including dyslipidemia, hemoglobinopathies such as thalassemia, hemolytic anemia, kidney failure and blood transfusions. Accordingly, extensive research has been conducted to find novel markers or mathematical methods of determining short-term glycemic variability including inter-day and intra-day variability which more closely monitor glycemic variability and hence would be more reliable indicators for hypoglycemia, microangiopathy and macroangiopathy-related complications [13].

Glycemic variability

Glycemic variability is defined as the fluctuations of glucose which occur throughout or between days, taking into consideration the amplitude, duration and frequency of glycemic excursions and has shown to statistically correlate with diabetes-related complications including hypoglycemia, macroangiopathies and microangiopathies [14].

Despite the numerous advantages posed by HbA1c for metabolic control in the long-term, it does not play a role in monitoring glycemic variability throughout the day or between days especially considering glycemic variability due to post-prandial peaks. Interestingly, some studies have shown that glycemic variability, and hence transient bouts of hypoglycemia and hyperglycemia cause elevated levels of oxidative stress compared to prolonged persistent hypo/hyperglycemia and thus are responsible for accelerated microangiopathy and macroangiopathy complications. The underlying pathophysiological mechanisms remain to be elucidated, however transient hyperglycemia induces oxidative stress by recruiting pro-inflammatory cytokines, while transient hypoglycemia induces endothelial damage by promoting platelet activation, both of which accelerate microangiopathy and macroangiopathy-related complications. This has stemmed researchers to overlook the mere HbA1c value and attempt to determine inter-day and intra-day variability, especially embraced by the advent of advanced diabetic technology devices such as CGM.

Glucose variability can be measured by performing CGM or self-monitored blood glucose to derive parameters which determine the amplitude and/or the timing of glycemic variability. The preferred approach by physicians of measuring glycemic variability is coefficient of variation defined as the standard deviation divided by the mean, which possesses the advantage of comparing the degree of variation between different data sets, hence is particularly useful in monitoring hypoglycemia [15].

Major limitations in achieving metabolic control

Incorrect carbohydrate counting

Carbohydrate counting (CC) is a meal planning practice for people with diabetes, focusing on tracking the amount of carbohydrates in grams consumed at meals to manage blood glucose (BG) levels. The correct bolus insulin dosage is determined by the total carbohydrate intake at each meal and the insulin-to-carbohydrate ratio (ICR). These two factors are used to estimate the amount of insulin required for the effective management of BG levels after each meal [16]. Evidence suggests that CC improves metabolic control and lowers HbA1c levels [17]. Thus, accurately performing CC is the recommended method to adjust insulin bolus and, consequently, to achieve proper BG regulation [18]. Indeed, carbohydrates over- and underestimations introduce errors in the bolus insulin that may lead to hypoglycemic and hyperglycemic episodes, respectively. Therefore, CC demands nutritional education and training and implementation of an individualized appropriate ICR [19].

Physical inactivity

Physical activity is being increasingly recommended as part of the therapeutic regimen for T1D because it helps to manage BG levels by reducing the risk of insulin resistance, weight gain or obesity [20]. Active adults with T1D demonstrated to achieve better blood pressure levels and lipid profile and to improve body composition, cardiorespiratory fitness, and well-being compared with their inactive counterparts [21]. Furthermore, in subjects with T1D at risk of diabetic kidney disease (DKD) or with established DKD, regular moderate-to-vigorous physical activity is associated with reduced incidence and progression of DKD, as well as reduced risk of cardiovascular events and mortality [22]. Physical inactivity can be a significant factor limiting the gain of good metabolic control and, therefore, exercise advice and physical activity assessment should become a routinary integral part of the patient-centered treatment strategy also in T1D [23]. In people with T1D, physical activity has been shown to reduce total daily insulin dose and HbA1c levels, but it exposes subjects to a greater risk of hypoglycemia. Furthermore, physical activity can make the estimate of the needed insulin dose even more challenging, with an overestimation of bolus after exercise and consequent risk of hypoglycemia [24].

Insulin physiology

Insulin, released by pancreatic β cells in response to increasing glucose levels, initially travels via the portal vein to the liver, interacting with hepatocytes. The portal vein delivers insulin to the liver in a pulsatile oscillatory pattern, occurring in intervals of approximately five minutes, with lower amplitude in pre-prandial conditions and higher amplitude in post-prandial states. The pulsatile pattern of portal vein-mediated insulin delivery enhances hepatic degradation of insulin and hence contributes to homeostasis, regulating the amount of insulin to maintain euglycemia in physiological states [25].

Exogenous insulin delivered by an insulin pump or insulin pen is administered subcutaneously and therefore does not undergo hepatic metabolism in the same manner as endogenous insulin, thereby decreasing the amount of insulin degradation. Consequently, exogenous insulin administration results in equal or excessive amount of insulin concentration relative to the portal vein, with consequent insulin activity in the adipose tissue and skeletal muscle rather than the liver, contributing to increased unwanted adverse effects such as weight gain and lipodystrophy. Furthermore, the absorption of insulin subcutaneously is a rate-limiting step of insulin activity since it takes time for insulin to cross into the blood circulation and exerts its metabolic effects in the periphery. The exogenous administration of insulin remains a major hindrance for improving glycemic control among people with T1D, and hence, novel methods of insulin administration should be studied to surmount this major limitation [7].

Fear of hypoglycemia and hypoglycemic unawareness

Hypoglycemia, defined as a glucose value below 70 mg/dL, poses a significant threat to people with T1D, since excessive repeated episodes of hypoglycemic bouts result in hypoglycemia unawareness, defined as the absence of symptoms with glucose below 70 mg/dL and is caused by a reduction the autonomic nervous system response threshold to further hypoglycemic events [8].

Such symptoms among individuals with diabetes may result in some subjects developing the so-called fear of hypoglycemia phenomenon, especially if the patient has had multiple episodes of symptomatic recurrent hypoglycemia. The phenomenon is characterized by anxiety and discomfort due to the fear of developing further hypoglycemic symptoms, which may result in somatization typically in the form of dyspnea, tremors, sweating and palpitations. Indeed, the fear of hypoglycemia phenomenon poses a significant threat for subjects since the symptoms mimic overt hypoglycemic symptoms, hence may result in inadequate metabolic control, and contribute to behaviors disproportionate to the actual risk of developing hypoglycemia [26]. Unfortunately, hypoglycemia is a common phenomenon occurring among people with T1D and constitutes an important barrier in achieving appropriate metabolic control if not appropriately managed [27].

Cutaneous reactions

Cutaneous reactions are common manifestations among people with diabetes which use insulin pens, insulin pumps and/or CGM. Some of the most reported skin reactions reported by insulin pump users include scar formation/fibrosis, pigmentation changes, erythema, and irritant/contact dermatitis. The dermatological manifestations may occur due to mechanical factors such as long-term cutaneous occlusion beneath the sensor, excessive local sweating, damaged epidermis due to plaster tearing or needle injury with insertion of the cannula. A cross-sectional study of 64 adolescent people with T1D showed how among adolescents with T1D using insulin pump therapy the most common skin complications were pigmentation changes and skin irritation [28].

Localized lipodystrophy arguably is one of the most common dermatological complications of people with diabetes which utilize insulin. Localized lipodystrophy can be defined as a group of disorders characterized by lipohypertrophy or lipoatrophy, denoting localized increase or retraction of subcutaneous fat respectively, due to insulin interaction with the panniculus. Indeed, subcutaneous insulin administration in sites of lipodystrophy results in poor absorption of insulin, thereby leading to hyperglycemia. Consequently, this typically results in the patient autonomously increasing the dosage of insulin to attempt to contrast the persistently elevated glycemic values. Accordingly, if the patient chooses a different injection site with the increased insulin dosage, then it will cause hypoglycemia and further contribute to poor metabolic control [29]. Cutaneous manifestations are often under-estimated by physicians and as such may have drastic consequences in acquiring the appropriate TIR, causing excessive glycemic fluctuations resulting in hyperglycemic or hypoglycemic excursions and hence contributing to poor metabolic control [9].

Diabulimia and eating disorders

Eating disorders are commonly encountered comorbidities among people with diabetes requiring insulin. Eating disorders among people with T1D are classified as overt eating disorders including bulimia nervosa or anorexia nervosa, and disordered eating symptoms which includes abnormal behaviors such as binge eating, excessive exercise, laxative or diuretic use, self-induced vomiting, and insulin therapy omission. These symptoms must be evaluated since may develop into overt eating disorders over time [30]. Accordingly, ‘diabulimia’ is a colloquial term often used by the media to denote the deliberate omission of insulin therapy to achieve weight loss. The rationale to omit insulin is to prevent weight gain due to the anabolic side effects of insulin and simultaneously achieve weight loss by inducing hyperglycemia which loses glucose calories by glucosuria [10].

Recent studies have demonstrated that eating disorders correlate with poor metabolic control and hence increased risk of diabetes-related complications. Despite the lack of formal diagnostic criteria, recent studies have suggested that approximately 20% of young women with T1D deliberately omit insulin [31].

The lack of formal diagnostic criteria and absent clinically validated tools poses a significant problem in screening people with diabetes with comorbid eating disorders or symptoms. Accordingly, physicians should screen for risk factors including female sex, adolescent age, overweight/obese body-mass index, excessive weight fluctuations, drug abuse, anxious personality trait and family history of alimentary disorders [32].

Double diabetes

Double diabetes was first described by Teupe and Bergin in 1991 and it denotes people with T1D which have concurrent clinical features of insulin resistance. Despite the suggested increasing prevalence of individuals affected by double diabetes, there are no clear-cut defining diagnostic criteria and hence the number of subjects affected globally remains largely unknown [33]. Nonetheless, double diabetes should be suspected in people with T1D with a family history of T2D, concurrent presence of obesity or metabolic syndrome, and insulin resistance measured by the Homeostatic Model Assessment for Insulin Resistance index, or the estimated glucose disposal rate [34]. Interestingly, people with double diabetes displayed a marked weight gain over time, a high daily insulin requirement and a positive family history of T2D. In addition, people with T1D with concurrent insulin resistance may have high normal blood pressure (or hypertension) and exhibit a higher cardiovascular risk [35].

The underlying pathophysiological mechanisms of insulin resistance in T1D remains to be elucidated, however, is thought to be caused by an increased incidence of obesity especially among younger people, due to lack of physical activity and excessive food consumption [36]. Furthermore, insulin resistance may be secondary to weight gain due to the anabolic effect of excessive subcutaneous insulin administration, that causes peripheral hyperinsulinemia and relative hepatic hypoinsulinemia compared to endogenous insulin [35].

Indeed, double diabetes constitutes an important obstacle in obtaining appropriate metabolic control especially given the lack of internationally recognized diagnostic criteria. Nonetheless, many studies are being conducted, especially regarding the role of new therapies used in T2D as potential adjuncts to insulin to ameliorate HbA1c, decrease glycemic variability, and decrease total daily insulin dose [34].

Potential adjunctive treatment in type 1 diabetes

Metformin

Metformin has long been considered and remains the gold standard first line treatment in people with T2D in conjunction with appropriate nutrition and physical exercise [37].

The principle of utilizing metformin as an adjunct to insulin therapy in T1D is to decrease glycemic variability especially by reducing post-prandial hyperglycemic excursions and decrease total daily insulin dose, particularly in persons with concurrent insulin resistance. The most important study coined the Reducing with Metformin Vascular Adverse Lesions (REMOVAL) trial, conducted in 2017 was a double-blind placebo-controlled trial which studied the effects of metformin in over 400 people with T1D on insulin therapy over a 3-year period. At the end of the 3 years, there was a total decrease of 0.13% HbA1c compared to baseline. Furthermore, insulin dose was reduced by approximately 0.02U/kg and weight loss of about 1.15 kg was achieved over a three-year period. Interestingly, there was no reported increased risk in ketoacidosis or hypoglycemic episodes, however, drop-out rates due to gastrointestinal symptoms were twice that of placebo and a reported higher incidence of people with vitamin B12 deficiency [38]. Accordingly, the use of metformin as an adjunctive therapy in people with T1D with concurrent insulin resistance remains unclear due to poor evidence in reducing HbA1c over time, however, it may be considered a useful additional therapy for subjects that require a reduction in total daily insulin dose and for those who are overweight or overtly obese or with other clinical signs of insulin resistance [39].

Glucagon-like peptide-1 receptor agonists

Glucagon like-peptide 1 receptor agonists (GLP-1-RA) are commonly prescribed treatments for people with T2D and are especially useful as an adjunct to metformin in people with overweight or obesity and are affected by cardiovascular atherosclerotic disease [40]. Furthermore, GLP-1-RA have been extensively studied in recent years and have been shown to stimulate weight loss, ameliorate insulin sensitivity and exhibit cardioprotective and nephroprotective effects [41].

The rationale of using GLP-1-RA in T1D may potentially be useful in reducing total daily insulin dose, promoting weight loss, decreasing hypoglycemic events, and lowering glycemic variability by reducing hyperglycemic excursions. Despite the clinical benefits of implementing GLP-1-RA in T2D with insulin therapy, albeit by decreasing HbA1c, decreasing hypoglycemia and inducing weight loss, recent clinical studies generally have not been successful in demonstrating a statistically significant reduction in HbA1c as adjunctive therapy in T1D. Despite the lack of amelioration in HbA1c parameter, recent clinical trials have shown that GLP-1-RA promote weight loss in people with T1D, typically in the range of approximately 4–7 kg compared to placebo over a 12–52-week period. Perhaps the most important randomized control trial analyzing the addition of GLP-1-RA to people with T1D was the Adjunct Therapy to Insulin in the Treatment of Type 1 Diabetes (ADJUNCT) study whereby over 1300 people with T1D received Liraglutide or placebo. Consistently, the ADJUNCT trial demonstrated a statistically significant weight loss and concurrent decrease in total daily insulin dose, especially at the higher doses of Liraglutide compared to the placebo. A statistically significant reduction of HbA1c was only demonstrated in the 1.2 mg Liraglutide dose. Furthermore, documented symptomatic hypoglycemic events were increased in Liraglutide at all doses compared to placebo and statistically significant increase in ketoacidosis in subjects treated with the highest dose of Liraglutide [42]. From the findings of the ADJUNCT trial and other trials, the addition of GLP-1-RA in people with T1D may be particularly useful in promoting weight loss and decreasing total daily insulin dose especially for those with concurrent insulin resistance. However, data is clearly lacking regarding ameliorations to HbA1c, glycemic variability, hypoglycemia risk and the incidence of adverse reactions including gastrointestinal symptoms or pancreatitis [43].

Sodium/glucose transporter 2 inhibitors

Sodium/Glucose transporter 2 inhibitors (SGLT2i) are relatively new therapeutic options typically used in people affected by T2D and especially indicated for people with concurrent heart failure or chronic kidney disease [44].

The use of SGLT2i in the management of T2D has been well documented and implemented in international guidelines, however, the use of SGLT2i in people with T1D is less clear. Nonetheless, the rationale of using SGLT2i includes reducing glycemic variability and hence ameliorating the TIR, decreasing the total daily insulin dose, promoting cardioprotective and nephroprotective effects and inducing weight loss, all of which without increasing the risk of hypoglycemic episodes. One of the major trials studying the use of SGLT2i in T1D was the Empaglifozin as Adunctive to Insulin Therapy in Type 1 Diabetes (EASE) trial, involving double-blind placebo-controlled trials comparing the effectiveness of different doses of Empaglifozin and placebo as adjuvant insulin therapy. Rather interestingly, the EASE trial demonstrated that the concurrent use of Empaglifozin with insulin therapy resulted in approximately 0.5% decrease in HbA1c, weight loss of approximately 2kg, and decreased the total daily insulin dose by approximately 0.1 U/kg compared to the placebo group after 28 days. Furthermore, blood pressure was reduced by approximately 4 mmHg systolic and 2 mmHg diastolic, and TIR improved by approximately 2 h per day [45].

Dapaglifozin Evaluation in Patients with Inadequately Controlled Type 1 Diabetes Trial (DEPICT-1) was a randomized placebo-controlled double-blind trial which compared Dapaglifozin at different doses and placebo as an adjunct to insulin therapy in subjects with T1D and inadequate glycemic control. Over 52 weeks, dapagliflozin led to improvements in glycemic control and weight loss in people with T1D, while increasing the risk of diabetic ketoacidosis (DKA) at approximately 4% compared to placebo [46].

Nonetheless, despite the potential use of Dapaglifozin in the treatment of T1D in addition to insulin therapy, its approval has been withdrawn by the Medicines and Healthcare Products Regulatory Agency (MHRA) and further longer studies are required before implementing SGLT2i with insulin due to the concurrent increased risk of diabetic ketoacidosis [47].

β cell preservation

Preservation of β cell function is a crucial goal in the management of T1D since it has been shown to promote metabolic control by reducing glycemic variability, decreasing hypoglycemic episodes, reduce risk of diabetic ketoacidosis and decrease the development of microangiopathies. C-peptide measurements is the gold-standard method to quantify residual pancreatic β cell function and correlates with the degree of metabolic control. Given its equimolar concentration with insulin and the longer half-life compared to insulin, it can be used as a reliable marker for residual β cell function among subjects with T1D [48].

A study conducted during the Diabetes Control and Complications Trial (DCCT) demonstrated the importance of β cell preservation in improving metabolic control, specifically by reducing HbA1c values, lowering the risks of diabetic retinopathy progression and decreasing the risk of severe hypoglycemic episodes. During this study, fasting and stimulated C-peptide following ingestion of a liquid mixed-meal were measured among subjects with a 1–5-year and 5–15-year duration of T1D. Among people with a 1–5-year duration, over an average of 6.5 years follow-up, C-peptide responders with stimulated C-peptide values ≥0.2 nmol/L had significantly lower values of HbA1c and blood glucose, and were receiving lower doses of insulin than the non-responders with C-peptide <0.2 nmol/L. In addition, C-peptide responder subjects assigned to intensive therapy had lower risks of both diabetic retinopathy progression and severe hypoglycemia compared with those receiving conventional treatment. In the intensive treatment group, for a 50% higher stimulated C-peptide on entry, such as from 0.10 to 0.15 nmol/L, HbA1c decreased by 0.07%, insulin dose decreased by 0.0276 units/kg/day and hypoglycemia risk decreased by 8.2%, while the risk of sustained retinopathy was reduced by 25% [49]. Thus, residual pancreatic β cell function, measured as stimulated C-peptide secretion, is associated with a reduced risk of long-term complications, hence highlighting the need to find new methods to preserve β cell function in newly diagnosed T1D.

A recently conducted randomized control trial has demonstrated that achievement of near-normal glucose levels soon in youths with newly diagnosed T1D has a positive impact on metabolic control, leading to a significant improvement in HbA1c values in the intensive diabetes management group compared with the standard care group. Nevertheless, intensive diabetes management did not affect the decline in pancreatic C-peptide secretion at 52 weeks [50]. Therefore, it is necessary to evaluate other methods to preserve β cell function in people with T1D either by implementing new diabetes technologies which mirror physiological pancreatic insulin secretion and/or adjunctive therapies to further improve metabolic control (Table 1).

Table 1.

Main factors that can interfere with the achievement of appropriate metabolic control, their features and appropriate management.

Major Limitations in Achieving Metabolic Control	Features	Management
Incorrect carbohydrate counting	It does not allow calculation of the appropriate prandial insulin bolus based on the number of carbohydrates consumed during the meal.	Implementation of an individualized appropriate insulin: carbohydrate ratio and education on carbohydrate counting.
Physical inactivity	It increases the risk of insulin resistance, weight gain or obesity.	Implementation of physical activity as a routine integral part of the patient-centered treatment strategy.
Inability to mirror endogenous pancreatic insulin secretion	Exogenous insulin does not follow the oscillatory portal-vein hepatic insulin delivery seen in the endogenous pancreas, leading to decreased hepatic-insulin degradation, and contributing to a state of euinsulinemia or hyperinsulinemia. This contributes to excessive insulin activity in the adipose tissue and skeletal muscle rather than the liver.	Use of advanced hybrid closed-loop systems which currently remains the best method of mirroring endogenous pancreatic function. Further research in new insulin-pump algorithms and dual-hormone pumps is required.
Hypoglycemia/Hypoglycemic Unawareness	Repeated episodes of hypoglycemia reduce the autonomic response to other hypoglycemic events; hence patients are more reluctant in administering insulin.	Education on how to manage hypoglycemia/hypoglycemic unawareness appropriately. Psychosocial counselling for patients with fear of hypoglycemia phenomenon.
Cutaneous manifestations	Localized insulin use and prolonged use of diabetes technology can lead to skin reactions that may lead to inadequate subcutaneous insulin absorption and poor glycemic control.	Ensure infusion sets and continuous glucose monitors are changed often. Rotate sites of injection/cannula and avoid areas of lipodystrophy.
Eating disorders or Diabulimia	Increasingly common among adolescents with type 1 diabetes and they correlate with poor metabolic control with higher rates of diabetic ketoacidosis and hypoglycemia.	Psychosocial screening and management for diabulimia and alimentary disorders.
Double Diabetes	Higher total daily doses of insulin are required which constitutes an important barrier in achieving appropriate metabolic control and further propagates insulin resistance.	Screening for clinical features of insulin resistance and use of adjunctive therapies: Metformin, GLP-1-RA or SGLT2i
β cell destruction in the natural course of type 1 diabetes	Declining pancreatic β cell function is associated with poorer metabolic control and increased diabetic complications.	Monitor residual β cell function by C-peptide measurements. Achieve euglycemia as much as possible to delay β cell decline.

Future prospects and conclusion

Appropriate metabolic control is a difficult target to achieve in people with T1D due to the increased incidence of people with concurrent insulin resistance, presence of dermatological manifestations, hypoglycemia/hypoglycemic unawareness with overt fear of recurring hypoglycemia, and comorbidities such as eating disorders. Therefore, it is crucial to develop new screening tools such as clinically validated questionnaires for fear of hypoglycemia, cutaneous reactions and alimentary disorders/symptoms, and internationally recognized indices for evaluating insulin resistance in subjects with T1D.

Nonetheless, perhaps the most important barrier to achieving appropriate metabolic control is the inability to appropriately mimic endogenous insulin secretion and mirror physiological portal vein oscillations. Nonetheless, advanced diabetic technology has attempted to surmount the obstacle with the development of CGM and insulin pumps. In particular, AHCL technology has permitted a significant improvement in metabolic control because it mimics the endogenous pancreas more physiologically compared to basal-bolus regimens, with various studies having demonstrated a significant improvement in glucose variability, ameliorated HbA1c, reduced risk of hypoglycemia, decreased total daily dose of insulin, and fewer microangiopathy and macroangiopathy-related complications. Despite the significant improvement in metabolic control by AHCL systems, there are still numerous barriers to overcome to mirror the physiological pancreas, including overcoming the non-linear relationship of subcutaneous insulin infusion and glycemic excursions particularly post-prandially. Furthermore, the subcutaneous administration of insulin does not resemble the physiological portal vein oscillations and hepatic metabolism, therefore contributes to the development of adverse reactions such as cutaneous manifestations and weight gain, and consequent poor metabolic control [7].

Various studies are being conducted to attempt to surmount this barrier including the development of new algorithms in insulin pumps, multiple-hormone pumps, and pulsed intravenous insulin therapy, all of which attempt to mirror insulin secretion more physiologically. Pulsed intravenous insulin therapy is still in early trials; however, the rationale is to mimic physiological pancreatic insulin secretion by administering insulin intravenously via a catheter in the portal vein, hence permitting appropriate hepatic first pass and second pass metabolism without the unwanted side effects of subcutaneous insulin. Nonetheless, it remains an invasive technique, and many further studies are required to better understand the benefits and possible side effects of implementing such treatment in daily clinical practice [51].

Currently utilized algorithms in AHCL pumps function by regulating the delivery of insulin doses based on the value indicated by the CGM. One such algorithm is the Proportional, Integrative, Derivative controller which modulates basal insulin doses based on the deviation from a pre-set target glucose value over a set-time period and calculating the area under the curve, however, lacks the ability to modulate non-linear glycemic kinetics such as post-prandial hyperglycemic peaks [52]. Another commonly utilized algorithm includes the Model Predictive Control which is an algorithm based on predicted glucose values over a given time range based on insulin doses and takes into consideration insulin stacking [53]. A recently developed algorithm is the so-called fuzzy logic, which utilizes intermediate metrics in a binary logic, considering glucose trends, current glucose levels, change in basal rate, quantity of insulin previously administered and therefore may be useful in predicting post-prandial hyperglycemic excursions and tardive hypoglycemia. Nonetheless, fuzzy logic controllers are technically difficult to implement, and more studies are required prior to use in clinical practice [54].

Dual-hormone pumps which potentially utilize other hormones such as glucagon as part of the insulin pump have been studied extensively in recent years. The rationale of utilizing dual-hormone pumps may contribute to better metabolic control by tackling the obstacles of single-pump therapy including post-prandial glycemic excursions and treating hypoglycemia without user intervention. However, glucagon would require a separate cartridge from the insulin pump, with the need to formulate room temperature-stable preparations to avoid fibril precipitation and necessitates extensive studies to fully understand the pharmacokinetics of subcutaneously administered glucagon. Furthermore, new algorithms would have to be implemented, especially considering the effect of different insulin: glucagon ratio on hepatic glucose production [53]. The development of new algorithms which take into consideration non-linear kinetic glycemic excursions coupled with dual-hormone pumps which can tackle predicted hypoglycemia would significantly improve metabolic control in people with T1D and contribute to an improved quality of life.

Author contributions

DP had the idea for the article, contributed to perform the literature search and critically revised the work. DP agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. LLP and FAM performed the literature search, data analysis and drafted the work. VP, MLL, AR, LT, MDL, FC, AB, LV and AP contributed to literature search. All authors read and approved the final version of the manuscript.

Funding

No funds, grants, or other support was received.

Competing interests

The authors declare no competing interests.