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Lipohypertrophy has been suggested as an outcome of lipogenic action of insulin and/or injection-related tissue trauma. In a cross-sectional study, we evaluated the predictors of lipohypertrophy in 372 type 1 diabetes patients (mean age 17.1 years) receiving subcutaneous insulin with pen and/or syringes for ≥3 months. On examining injection sites with inspection and palpation technique, 62.1% patients demonstrated lipohypertrophy. Univariate analysis showed that gender, BMI, HbA1c, injection device, rotation, injection area, needle length, insulin regimen, and total daily dose of insulin were associated with lipohypertrophy (p < 0.05). Notably, the mean needle reuse was comparable in patients with or without lipohypertrophy (8.1 vs. 7.2, p = 0.534). In multivariate logistic regression, gender, HbA1c, TDD, injection devices, and needle length lost its significance. Further, injections over smaller area (≤8.5 × 5.5 cm) and non-rotation of sites were found to be strongest independent predictor of lipohypertrophy (p < 0.0005 for both) with increased odds of 23.2 (95% CI 9.1–59.2) and 6.3 (95% CI 3.4–11.9) times, respectively. Being underweight was also a significant independent predictor (odds ratio [OR] 13.0 [95% CI 2.2–75.2], p = 0.004). Compared to rapid plus long-acting analogs, regular insulin plus long-acting analogs and conventional premixed insulin users had 3.2 (95% CI 1.5–6.8, p = 0.003) and 4.6 (95% CI 1.4–15.7, p = 0.014) fold higher risk of lipohypertrophy (mean injection frequency 4.01 vs. 4.01 vs. 2.09, respectively). Sub-group analysis showed that lipohypertrophy was 79% less likely in patients with multiple daily injections (≥4) than twice-daily regimen (OR 0.21, p < 0.0005). Moreover, lipohypertrophy was reduced to half with bolus doses of rapid-acting insulin analogs than regular insulin (p = 0.003), even though mean injection frequency was comparable (4.01 vs. 3.93, p = 0.229). This difference was statistically insignificant for basal doses with NPH or long-acting analogs (p = 0.069). Therefore, injection area, rotation, BMI, and insulin regimen are the best predictors of lipohypertrophy and together could correctly identify lipohypertrophy status in 84.4% patients with excellent discrimination capability (AUC = 0.906, p < 0.0005). In conclusion, findings of our study suggest that delivering rapidly absorbed insulin analogs over large injection area along with greater split of total daily doses reduce insulin-induced lipogenesis and outplay tissue trauma added through frequent injections and needle reuse.

A 56-year-old middle-eastern male with a long-standing history of poorly controlled type 2 diabetes mellitus presented to us complaining of severely painful bilateral upper and lower extremity cramps occurring shortly after his rapid-acting insulin analog injection(s). The cramps had started 6 months ago and have been occurring intermittently in non-predictable episodes since then. He had otherwise never experienced any insulin-related adverse reaction(s) before. His cramps are very painful and debilitating, interfering with his daily activities and placing him in a state of constant fear/anxiety of re-experiencing them. This caused him to become non-adherent with his prescribed treatment and poorly compliant with his follow-up regimens. Thorough examination showed a diffuse loss of sensation over the lower limbs. This was subsequently confirmed with a combined electromyography–nerve conduction study which indicated extensive diabetic axonal polyneuropathy. By contrast, lower extremity segmental arterial pressures were negative for peripheral vasculo-occlusive disease, ruling out vascular insufficiency as a possible etiology of the cramps. We then measured the levels of serum electrolytes right-before and 30 min right-after injecting the patient with his insulin. Potassium dropped by about 16% from its initial level, compared to a drop of only around 4% for calcium and none (0%) for magnesium. Thus, we speculated this insulin-induced sharp drop in serum potassium levels as potentiating the patient’s already existing advanced diabetic neuropathy, thereby leading to muscle cramping. However, attempting potassium supplementation for a brief period of time led to a rapid resolution of cramps when they occurred and an overall reduction in their frequency of recurrence. This tilted our diagnosis toward the insulin-induced acute drop in serum potassium levels as the most likely etiology underlying the patient’s cramps. Such an observation has been made only once previously within the literature, back in 1992, at the Duke University Medical Center.

A 56-year-old middle-eastern male with a long-standing history of poorly controlled type 2 diabetes mellitus presented to us complaining of severely painful bilateral upper and lower extremity cramps occurring shortly after his rapid-acting insulin analog injection(s). The cramps had started 6 months ago and have been occurring intermittently in nonpredictable episodes since then. He had otherwise never experienced any insulin-related adverse reaction(s) before. His cramps are very painful and debilitating, interfering with his daily activities and placing him in a state of constant fear/anxiety of re-experiencing them. This caused him to become non-adherent with his prescribed treatment and poorly compliant with his follow-up regimens. Thorough examination showed a diffuse loss of sensation over the lower limbs. This was subsequently confirmed with a combined electromyography-nerve conduction study which indicated extensive diabetic axonal polyneuropathy. By contrast, lower extremity segmental arterial pressures were negative for peripheral vasculo-occlusive disease, ruling out vascular insufficiency as a possible etiology of the cramps. We then measured the levels of serum electrolytes right-before and 30 min right-after injecting the patient with his insulin. Potassium dropped by about 16% from its initial level, compared to a drop of only around 4% for calcium and none (0%) for magnesium. Thus, we speculated this insulin-induced sharp drop in serum potassium levels as potentiating the patient's already existing advanced diabetic neuropathy, thereby leading to muscle cramping. However, attempting potassium supplementation for a brief period of time led to a rapid resolution of cramps when they occurred and an overall reduction in their frequency of recurrence. This tilted our diagnosis toward the insulin-induced acute drop in serum potassium levels as the most likely etiology underlying the patient's cramps. Such an observation has been made only once previously within the literature, back in 1992, at the Duke University Medical Center. [ABSTRACT FROM AUTHOR]

The insulin receptor (IR) is a tyrosine kinase receptor that can mediate both metabolic and mitogenic biological actions. The IR isoform-A (IR-A) arises from alternative splicing of exon 11 and has different ligand binding and signaling properties compared to the IR isoform-B. The IR-A not only binds insulin but also insulin-like growth factor-II (IGF-II) with high affinity. IGF-II acting through the IR-A promotes cancer cell proliferation, survival, and migration by activating some unique signaling molecules compared to those activated by insulin. This observation led us to investigate whether the different IR-A signaling outcomes in response to IGF-II and insulin could be attributed to phosphorylation of a different subset of IR-A tyrosine residues or to the phosphorylation kinetics. We correlated IR-A phosphorylation to activation of molecules involved in mitogenic and metabolic signaling (MAPK and Akt) and receptor internalization rates (related to mitogenic signaling). We also extended this study to incorporate two ligands that are known to promote predominantly mitogenic [(His4, Tyr15, Thr49, Ile51) IGF-I, qIGF-I] or metabolic (S597 peptide) biological actions, to see if common mechanisms can be used to define mitogenic or metabolic signaling through the IR-A. The threefold lower mitogenic action of IGF-II compared to insulin was associated with a decreased potency in activation of Y960, Y1146, Y1150, Y1151, Y1316, and Y1322, in MAPK phosphorylation and in IR-A internalization. With the poorly mitogenic S597 peptide, it was a decreased rate of tyrosine phosphorylation rather than potency that was associated with a low mitogenic potential. We conclude that both decreased affinity of IR-A binding and kinetics of IR-A phosphorylation can independently lead to a lower mitogenic activity. None of the studied parameters could account for the lower metabolic activity of qIGF-I. [ABSTRACT FROM AUTHOR]

In view of the lifelong exposure and large patient populations involved, insulin analogs with an increased mitogenic effect in comparison to human insulin may potentially constitute a major health problem, since these analogs may possibly induce the growth of pre-existing neoplasms. At present, the available data suggest that insulin analogs are safe. In line with these findings, we observed that serum of diabetic patients treated with insulin analogs, compared to that of diabetic patients treated with human insulin, did not induce an increased phosphorylation of tyrosine residues of the insulin-like growth factor-I receptor (IGF-IR). However, the classical model of the IGF-IR signaling may be insufficient to explain (all) mitogenic effects of insulin analogs since also non-canonical signaling pathways of the IGF-IR may play a major role in this respect. Although phosphorylation of tyrosine residues of the IGF-IR is generally considered to be the initial activation step within the intracellular IGF-IR signaling pathway, it has been found that cells undergo a signaling switch under hyperglycemic conditions. After this switch, a completely different mechanism is utilized to activate the mitogenic (mitogen-activated protein kinase) pathways of the IGF-IR that is independent from tyrosine phosphorylation of the IGF-IR. At present it is unknown whether activation of this alternative intracellular pathway of the IGF-IR occurs during hyperglycemia in vivo and whether it is stronger in patients treated with (some) insulin analogs than in patients treated with human insulin. In addition, it is unknown whether the insulin receptors (IRs) also undergo a signaling switch during hyperglycemia. This should be investigated in future studies. Finally, relative overexpression of IR isoform A (IR-A) in (pre) cancer tissues may play a key role in the development and progression of human cancers during treatment with insulin (analogs). Further studies are required to unravel whether the IR-A is involved in the development of cancers and whether, in this respect (some) insulin analogs differ from human insulin. [ABSTRACT FROM AUTHOR]

Today, insulin analogs are used in millions of diabetic patients. Insulin analogs have been developed to achieve more physiological insulin replacement in terms of time course of the effect. Modifications in the amino acid sequence of the insulin molecule change the pharmacokinetics and pharmacodynamics of the analogs in respect to human insulin. However, these changes can also modify the molecular and biological effects of the analogs. The rapid-acting insulin analogs, lispro, aspart and glulisine, have a rapid onset and shorter duration of action. The long-acting insulin analogs glargine and detemir have a protracted duration of action and a relatively smooth serum concentration profile. Insulin and its analogs may function as growth factors and therefore have a theoretical potential to promote tumor proliferation. A major question is whether analogs have an increased mitogenic activity in respect to insulin. These ligands can promote cell proliferation through many mechanisms like the prolonged stimulation of the insulin receptor, stimulation of the IGF-1 receptor (IGF-1R), prevalent activation of the ERK rather than the AKT intracellular post-receptor pathways. Studies on in vitro models indicate that short-acting analogs elicit molecular and biological effects that are similar to those of insulin. In contrast, long-acting analogs behave differently. Although not all data are homogeneous, both glargine and detemir have been found to have a decreased binding to IR but an increased binding to IGF-1R, a prevalent activation of the ERK pathway, and an increased mitogenic effect in respect to insulin. Recent retrospective epidemiological clinical studies have suggested that treatment with long-acting analogs (specifically glargine) may increase the relative risk for cancer. Results are controversial and methodologically weak. Therefore prospective clinical studies are needed to evaluate the possible tumor growth-promoting effects of these insulin analogs.

Today, insulin analogs are used in millions of diabetic patients. Insulin analogs have been developed to achieve more physiological insulin replacement in terms of time-course of the effect. Modifications in the amino acid sequence of the insulin molecule change the pharmacokinetics and pharmacodynamics of the analogs in respect to human insulin. However, these changes can also modify the molecular and biological effects of the analogs. The rapid-acting insulin analogs, lispro, aspart, and glulisine, have a rapid onset and shorter duration of action. The long-acting insulin analogs glargine and detemir have a protracted duration of action and a relatively smooth serum concentration profile. Insulin and its analogs may function as growth factors and therefore have a theoretical potential to promote tumor proliferation. A major question is whether analogs have an increased mitogenic activity in respect to insulin. These ligands can promote cell proliferation through many mechanisms like the prolonged stimulation of the insulin receptor, stimulation of the IGF-1 receptor (IGF-1R), prevalent activation of the extracellular-signaling-regulated kinase (ERK) rather than the protein kinase B (PKB/AKT) intracellular post-receptor pathways. Studies on in vitro models indicate that short-acting analogs elicit molecular and biological effects that are similar to those of insulin. In contrast, long-acting analogs behave differently. Although not all data are homogeneous, both glargine and detemir have been found to have a decreased binding to receptors for insulin but an increased binding to IGF-1R, a prevalent activation of the ERK pathway, and an increased mitogenic effect in respect to insulin. Recent retrospective epidemiological clinical studies have suggested that treatment with long-acting analogs (specifically glargine) may increase the relative risk for cancer. Results are controversial and methodologically weak. Therefore prospective clinical studies are needed to evaluate the possible tumor growth-promoting effects of these insulin analogs.