Insulin treatment has many cutaneous alterations and skin-related adverse effect, lipohypertrophy (LH) is the commonest among them. LH has the definition with a tumor-like lump, visible and touchable, adipose tissue at the site of insulin injection. It might result from the lipogenic effect of repeated insulin exposure.[3,4] Injecting insulin into the tissue with LH weakens insulin physiological function, and leads to a resulting excess glucose exposure, glycemic modifiability, and an increased risk of hypoglycemia. Unfortunately, there is limited information about the pathophysiology of LH in insulin users. As a result, reports of prevalence, clinical consequence, and pathogenesis are needed.
The epidemiological data about LH have shown large differences in prevalence rate. Even in recent 5 years, the prevalence rate of LH in insulin users ranges broadly from 11.1% to 73.4%. In China, the reported prevalence ranges from 53.1% to 73.4%.[6–8]
The gold standard for the detection of LH is ultrasonic skin scanning, revealing an increased echo of the subcutaneous tissue, and with or without different sizes of the definite nodules in the boundary area.[9,10] Besides, histopathological biopsy is a reliable method to detect LH, and it can prevent an amyloid mass from being misdiagnosed as LH. However, for economic and practical reasons, most studies have relied on observing and palpating. The vast difference of prevalence rate could be due to the detection capacity of different inspection staffs.
In fact, the highly variable morphological characteristics of LH in terms of size, texture, and prominence of the skin also make diagnosis difficult [Table 1]. Gentile et al provides a detailed way to identify lesions: the research staff were advised to apply pressure when they noticed a hardening of the skin, confirming first impressions by comparing the thickness of the suspicious area with the thickness of the surrounding area. Then, performing repeated vertical and horizontal fingertip movements over and around it, pinch maneuvering, and marking it. By repeating the above palpation, most smaller, flatter lesions are easily identified and measured.[9,10]
A research conducted in Spain recorded severe unknown hypoglycemia in 49.1% of insulin users with LH, whereas in diabetics without LH, this rate was 5.9% to 6.5%. Patients with LH have an almost seven-fold to 13-fold higher occurrence of glycemic variability compared with person without LH.[12,13]
In fact, it is easy to understand why injecting insulin into lipohypertrophic tissues is associated with large glycemic excursions and poor metabolic control based on pharmacokinetics and pharmacodynamics. LH is characterized by thickened hard elastic adipose tissue with large adipocytes and dense fibrous texture. Its structural properties make insulin release slower and unpredictable. A study compared liphypertrophic tissue and normal adipose tissue and showed that there was a separation of the postmeal blood glucose curves after 30 min leading to significant differences in blood glucose levels from 2 h onwards, and in maximum postprandial blood glucose concentrations.
Poor glycemic control can increase the risk of various complications of diabetes mellitus, such as cardiovascular disease,[15,16] diabetic foot, retinal disease,[18,19] kidney disease, and so on. Additionally, patients prefer reutilizing lipohypertrophic areas for injection due to pain reduction. It could increase insulin consumption, medical expenses, and financial burdens on families and communities.[12,21]
The pathogenesis of insulin-related LH is still unclear. Among various proposed mechanisms, it seems that LH is a local effect caused by the reaction of adipocytes to the insulin injection. But the susceptibility of LH varies widely, so other immunological factors are possibly involved. A study in Europe showed that the level of anti-insulin antibody had a positive relationship with LH. Usually, the anti-insulin antibodies are IgG or IgE antibodies. Several factors influence the production of anti-insulin antibodies, such as genetics, the purity of insulin, the source of insulin, insulin species, mode of administration, and so on.
On the other hand, insulin has an anabolic effect on local adipocytes, promoting the synthesis of fats and proteins; these may cause the occurrence of LH. Notably, patients using regular insulin had a 3.2-fold risk of LH than those using fast insulin for the same average insulin injection frequency. This observation could be due to the faster absorption from the relatively higher number of insulin monomers contained in the rapid-acting insulin analogs compared with regular insulin. Due to improved pharmacokinetic actions, rapid-acting insulin analogs, in contrast to conventional insulin, are likely to prevent adipocytes from the lipogenic action.
Already known risk factors of LH include high body mass index, frequency of needle reuse, failure to alternate injection sites and internal rotations, frequency of daily injections, length of the needle, duration of insulin therapy, high hemoglobin A1c, and patients with hypoglycemia.[8,12,25,26] Patients’ behaviors play a significant role in LH, since patients prefer reusing less painful tissue and more promptly accessible sites.
Altogether, these mechanisms have a certain impact on the occurrence of LH, but additional research is needed to unravel a clear pathophysiological mechanism of LH in insulin users.
Specific treatment of LH is still unavailable because the pathophysiological mechanism of LH has not been fully understood. Liposuction has been tried as a therapeutic treatment, but it can only alleviate the symptoms. Proper insulin administration technique, avoiding insulin injection at lipohypertrophic areas, and rotation of injection sites can reduce LH size over time.[28,29]
In conclusion, prevention and appropriate follow-up should take the first place in the management of these patients. It is imperative for medical staff to teach patients the correct method of insulin injection during treatment. Not only that, LH should be checked at the injection site as a part of the annual review for insulin users.
Conflicts of interest
1. Gentile S, Strollo F, Ceriello A. Lipodystrophy in insulin-treated subjects and other injection-site skin reactions: are we sure everything is clear? Diabetes Ther
2016; 7:401–409. doi: 10.1007/s13300-016-0187-6.
2. Sürücü HA, OKA H. Lipohypertrophy in Individuals with type 2 diabetes: prevalence and risk factors. J Caring Sci
2018; 7:67–74. doi: 10.15171/jcs.2018.011.
3. Barola A, Tiwari P, Bhansali A, Grover S, Dayal D. Insulin-related lipohypertrophy: lipogenic action or tissue trauma? Front Endocrinol (Lausanne)
2018; 9:638doi: 10.3389/fendo.2018.00638.
4. Abu Ghazaleh H, Hashem R, Forbes A, Dilwayo TR, Duaso M, Sturt J, et al. A systematic review of ultrasound-detected lipohypertrophy in insulin-exposed people with diabetes. Diabetes Ther
2018; 9:1741–1756. doi: 10.1007/s13300-018-0472-7.
5. Famulla S, Hövelmann U, Fischer A, Coester HV, Hermanski L, Kaltheuner M, et al. Insulin injection into lipohypertrophic tissue: blunted and more variable insulin absorption and action and impaired postprandial glucose control. Diabetes Care
2016; 39:1486–1492. doi: 10.2337/dc16-0610.
6. Patil M, Sahoo J, Kamalanathan S, Selviambigapathy J, Balachandran K, Kumar R, et al. Assessment of insulin injection techniques among diabetes patients in a tertiary care centre. Diabetes Metab Syndr
2017; 11:S53–S56. doi: 10.1016/j.dsx.2016.09.010.
7. Li FF, Fu SM, Liu ZP, Liu XR, Hu CJ, Li QF. Injection sites lipohypertrophy among 736 patients with type 2 diabetes of different-grade hospitals. Int J Clin Exp Med
8. Ji L, Sun Z, Li Q, Qin G, Wei Z, Liu J, et al. Lipohypertrophy in China: prevalence, risk factors, insulin consumption, and clinical impact. Diabetes Technol Ther
2017; 19:61–67. doi: 10.1089/dia.2016.0334.
9. Gentile S, Guarino G, Giancaterini A, Guida P, Strollo F. A suitable palpation technique allows to identify skin lipohypertrophic lesions in insulin-treated people with diabetes. Springerplus
2016; 5:563doi: 10.1186/s40064-016-1978-y.
10. Bertuzzi F, Meneghini E, Bruschi E, Luzi L, Nichelatti M, Epis O. Ultrasound characterization of insulin induced lipohypertrophy in type 1 diabetes mellitus. J Endocrinol Invest
2017; 40:1107–1113. doi: 10.1007/s40618-017-0675-1.
11. Nilsson MR. Insulin amyloid at injection sites of patients with diabetes. Amyloid
2016; 23:139–147. doi: 10.1080/13506129.2016.1179183.
12. Blanco M, Hernandez MT, Strauss KW, Amaya M. Prevalence and risk factors of lipohypertrophy in insulin-injecting patients with diabetes. Diabetes Metab
2013; 39:445–453. doi: 10.1016/j.diabet.2013.05.006.
13. Gentile S, Strollo F, Della TC, Marino G, Guarino G. Skin complications of insulin injections: a case presentation and a possible explanation of hypoglycaemia. Diabetes Res Clin Pract
2018; 138:284–287. doi: 10.1016/j.diabres.2018.02.005.
14. Gradel AKJ, Porsgaard T, Lykkesfeldt J, Seested T, Gram-Nielsen S, Kristensen NR, et al. Factors affecting the absorption of subcutaneously administered insulin: effect on variability. J Diabetes Res
2018; 2018:1205121doi: 10.1155/2018/1205121.
15. Low Wang CC, Hess CN, Hiatt WR, Goldfine AB. Clinical update: cardiovascular disease in diabetes mellitus: atherosclerotic cardiovascular disease and heart failure in type 2 diabetes mellitus - mechanisms, management, and clinical considerations. Circulation
2016; 133:2459–2502. doi: 10.1161/circulationaha.116.022194.
16. Fox CS, Golden SH, Anderson C, Bray GA, Burke LE, de Boer IH, et al. Update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care
2015; 38:1777–1803. doi: 10.2337/dci15-0012.
17. Noor S, Khan RU, Ahmad J. Understanding diabetic foot infection and its management. Diabetes Metab Syndr
2017; 11:149–156. doi: 10.1016/j.dsx.2016.06.023.
18. Stem MS, Dunbar GE, Jackson GR, Farsiu S, Pop-Busui R, Gardner TW. Glucose variability and inner retinal sensory neuropathy in persons with type 1 diabetes mellitus. Eye (Lond)
2016; 30:825–832. doi: 10.1038/eye.2016.48.
19. Lu J, Ma X, Zhang L, Mo Y, Ying L, Lu W, et al. Glycemic variability assessed by continuous glucose monitoring and the risk of diabetic retinopathy in latent autoimmune diabetes of the adult and type 2 diabetes. J Diabetes Investig
2019; 10:753–759. doi: 10.1111/jdi.12957.
20. Fu H, Liu S, Bastacky SI, Wang X, Tian XJ, Zhou D. Diabetic kidney diseases revisited: a new perspective for a new era. Mol Metab
2019; 30:250–263. doi: 10.1016/j.molmet.2019.10.005.
21. Ji L, Chandran A, Inocencio TJ, Sun Z, Li Q, Qin G, et al. The association between insurance coverage for insulin pen needles and healthcare resource utilization among insulin-dependent patients with diabetes in China. BMC Health Serv Res
2018; 18:300doi: 10.1186/s12913-018-3095-9.
22. Hajheydari Z, Kashi Z, Akha O, Akbarzadeh S. Frequency of lipodystrophy induced by recombinant human insulin. Eur Rev Med Pharmacol Sci
23. Petersen MC, Shulman GI. Mechanisms of insulin action and insulin resistance. Physiol Rev
2018; 98:2133–2223. doi: 10.1152/physrev.00063.2017.
24. Baruah MP, Kalra S, Bose S, Deka J. An audit of insulin usage and insulin injection practices in a large Indian cohort. Indian J Endocrinol Metab
2017; 21:443–452. doi: 10.4103/ijem.IJEM_548_16.
25. Al Ajlouni M, Abujbara M, Batieha A, Ajlouni K. Prevalence of lipohypertrophy and associated risk factors in insulin-treated patients with type 2 diabetes mellitus. Int J Endocrinol Metab
2015; 13:e20776doi: 10.5812/ijem.20776.
26. Tandon N, Kalra S, Balhara YP, Baruah MP, Chadha M, Chandalia HB, et al. Forum for injection technique (FIT), India: the Indian recommendations 2.0, for best practice in insulin injection technique, 2015. Indian J Endocrinol Metab
2015; 19:317–331. doi: 10.4103/2230-8210.152762.
27. Singha A, Bhattarcharjee R, Ghosh S, Chakrabarti SK, Baidya A, Chowdhury S. Concurrence of lipoatrophy and lipohypertrophy in children with type 1 diabetes using recombinant human insulin: two case reports. Clin Diabetes
2016; 34:51–53. doi: 10.2337/diaclin.34.1.51.
28. Campinos C, Le Floch JP, Petit C, Penfornis A, Winiszewski P, Bordier L, et al. An effective intervention for diabetic lipohypertrophy: results of a randomized, controlled, prospective multicenter study in France. Diabetes Technol Ther
2017; 19:623–632. doi: 10.1089/dia.2017.0165.
29. Smith M, Clapham L, Strauss K. UK lipohypertrophy interventional study. Diabetes Res Clin Pract
2017; 126:248–253. doi: 10.1016/j.diabres.2017.01.020.