CME INDIA Case Presentation by Dr. Gururaj B. Sattur, MD, MRCP (UK), FICC, Senior Physician and Diabetologist, Hubli, Karnataka; Chairman API – Karnataka State Chapter (2018-19); Member of COVID Expert Committee, Karnataka.

CME INDIA Case Study

• 35-year-old Type 1 diabetic female.
• History of T1DM for last 18+ yrs.
• IT sector job.
• After marriage, 2 pregnancies successfully managed.
• No maternal or foetal problems.
• HbA1c 6.4 to 6.8 at all times.

Comments in CME INDIA

Dr. N. K. Singh:

• She must be on Insulin so most important consideration is Insulin Lipodystrophy.
• However, we should be aware that it could be acquired generalized lipodystrophy (AGL), it is marked by severe insulin resistance and hypertriglyceridemia. Rarely, AGL and type 1 diabetes coexist.
• We need more history: How long/ Symptoms/HB1ac/HOMA IR/SERUM LEPTIN/LIPIDS?

Dr. Deepak Rastogi, Kotdwara, Uttarakhand:

• Is she on insulin? If so, it seems to be Insulin induced Lippo hypertrophy or Lipoma

Dr. Anuj Kr. Baruah, Gauhati:

• Looks like Insulin lipodystrophy!
• What else as D/D?
• Diabetic amyotrophy.

Dr. G. B. Sattur, Hubli:

• She is T1DM last 18+ yrs.  IT graduate. Lives in a metro city after marriage. 
• 2 pregnancies successfully managed. No maternal or foetal problems.
• On Basal Bolus Insulin regime.
• HbA1c 6.4 to 6.8 at all times.
• However, during 2nd pregnancy, I didn’t know, what went into her head, started taking insulin in upper outer quadrant of both thighs ONLY (found difficult to reach front thighs), for 1 yr. or so.
• It’s insulin Lipohypertrophy.
• The elevated areas of thighs are partially firm and indurated.
• Refereed for Liposuction to a plastic surgeon.
• In our clinic in Hubli, (her mother’s place,) injection sites are examined on every visit.

Dr. N. K. Singh:

• History clears all myths

CME INDIA Learning Points

• Lipodystrophy (LD) is a well-known complication of subcutaneous insulin injections. It can manifest as either lipohypertrophy (LH) or lipoatrophy (LA). Lipoatrophy refers to the development of deep, retracted scars on the skin due to damage to subcutaneous fatty tissue.
• Lipohypertrophy (LH) is characterized by the development of thickened, rubbery tissue swellings at injection sites. These swellings are mostly firm but can occasionally present as soft lesions as well. Due to its nature, LH can be easily missed during a standard medical examination.
• While the exact cause of LH is not fully understood, several local factors are believed to contribute to its development:
  • Insulin’s growth-promoting properties: The insulin molecule itself has strong growth-promoting properties. Prolonged exposure to insulin at the same injection site can lead to the growth of adipose tissue, resulting in lipohypertrophy.
  • Repeated trauma from poor injection habits: Poor injection habits, such as infrequent or missed injection site rotation and frequent needle reuse, can cause repeated trauma to the subcutaneous tissue. This trauma contributes to the development of lipohypertrophic lesions.
  • In addition to these local factors, several other factors have been associated with the development of lipohypertrophy:

• It’s important for healthcare providers and individuals with diabetes to be aware of these factors and take steps to minimize the risk of developing LH.
• Proper injection technique, regular rotation of injection sites, and avoiding needle reuse are important strategies to prevent lipohypertrophy. Regular monitoring and examination of injection sites can also help in early detection and management of lipohypertrophic lesions. Proper injection technique, appropriate site rotation, and avoiding injection into areas with lipodystrophic changes are important measures to prevent these complications and maintain stable glycemic control.

Are LH and LA synonymous?

• While lipohypertrophy (LH) and lipoatrophy (LA) are related complications of subcutaneous insulin injections, they are not synonymous. LH refers to the thickened, rubbery tissue swelling at injection sites, while LA is characterized by retracted scars and loss of subcutaneous fatty tissue.
• It is crucial for healthcare providers to differentiate between LH and LA and accurately diagnose lipodystrophy to ensure appropriate management and minimize the risk of glycemic imbalances.
• Insulin-induced lipohypertrophy remains a frequent complication of insulin injection. It has been reported as 49% in people with insulin-treated T2DM and 34% in people with T1DM in a recent meta-analysis. (Ref-5)
• Subcutaneous adipose tissue has been known to be a local target of exogeneous insulin action since 1950.
• While LH is most commonly seen in those with poor injection technique since the discovery of insulin.
• LA was commonly found before the 1970s when impure animal insulin was used.
• With the availability of recombinant insulin, the prevalence of LA has been reported at only 0.2–1.4%. (Ref-7)

Clinical Grading of LH

• A clinical grading of LH may be applied. (Ref-6)
• Grade 1: lipohypertrophy without visible skin lesion but increased palpable density of subcutaneous tissue.
• Grade 2: severe hypertrophy with increased density of the injection site.

Does a missed diagnosis of lipodystrophy (LD) can have significant clinical consequences.?

• When insulin is injected into areas affected by LD, it can lead to wide fluctuations in blood glucose levels. Studies have indicated that insulin absorption at areas affected by lipohypertrophy (LH) can be delayed and erratic, leading to challenges in achieving optimal metabolic control. This can result in the need for higher doses of insulin to achieve the desired glycemic control, which further contributes to glucose oscillations and instability.
• These fluctuations may include inappropriately high glucose levels and an increased rate of unexplained hypoglycemic episodes. (Rebound Hypoglycemias).
• Importantly, these glycemic oscillations may not respond adequately to changes in insulin dosage.
• From an economic perspective, the burden of the disease increases for both patients and the healthcare system. The need for higher insulin doses, increased monitoring, and potential complications associated with poor glycemic control can lead to higher healthcare costs and decreased quality of life for patients.

It is crucial to systematically identify as many areas affected by LH as possible.

• By recognizing and understanding the presence of lipohypertrophic sites, healthcare providers can educate patients on good insulin injection habits. This includes proper site rotation, avoidance of injecting into affected areas, and techniques to promote optimal insulin absorption.
• Improved education and awareness regarding LH can help patients achieve better glycemic control, reduce the risk of hypoglycemic episodes, and alleviate the economic burden associated with managing the disease.

Unusual Facts

• In the extreme cases, insulin-derived localized amyloidosis or “insulin ball” could develop.
• In such cases cosmetic surgery is required to manage this cutaneous complication.
• The role of imaging including ultrasound and CT scan could differentiate insulin-derived localized amyloidosis from the more common insulin-induced LH.
• Recognizing this rare insulin reaction and timely detection of lipoatrophy with ultrasound as a non-invasive simple imaging modality is necessary to avoid further injection in the skin lesion.
• Specific treatment of LA is still unavailable.
• Therapeutic trials of dexamethasone and cromolyn sodium had been reported successfully in the anecdotal cases.

What about needles?

• Apart from poor injection techniques, insulin devices and needles might also play a role in the development of LH.
• Faulty devices and needles lead to possible greater tissue injury from mismatch devices and repetitive uses.
• Theoretically, needle lengths should be as short as possible to minimize tissue trauma and to avoid inadvertent intramuscular administration, especially in skinny people.

CME INDIA Tail Piece

“The irregular insulin absorption associated with LH can lead to a higher risk of serious hypoglycemic episodes followed by rebound hyperglycemia when patients switch from affected injection sites to unaffected ones. These glucose fluctuations pose significant challenges in achieving stable glycemic control and can have detrimental effects on patients’ overall metabolic health.”

References:

1. Gentile S, Strollo F, Ceriello A; AMD-OSDI Injection Technique Study Group. Lipodystrophy in Insulin-Treated Subjects and Other Injection-Site Skin Reactions: Are We Sure Everything is Clear? Diabetes Ther. 2016 Sep;7(3):401-9. doi: 10.1007/s13300-016-0187-6. Epub 2016 Jul 25. PMID: 27456528; PMCID: PMC5014793.
2. Perciun R. Ultrasonographic aspect of subcutaneous tissue dystrophies as a result of insulin injections. Med Ultrason. 2010;12:104–109.
3. Al-Hayek AA, Robert AA, Braham RB, Al-Dawish MA. Frequency of lipohypertrophy and associated risk factors in young patients with type 1 diabetes: a cross-sectional study. Diabetes Ther. 2016
4. Thewjitcharoen Y, Prasartkaew H, Tongsumrit P, et al. Prevalence, Risk Factors, and Clinical Characteristics of Lipodystrophy in Insulin-Treated Patients with Diabetes: An Old Problem in a New Era of Modern Insulin. Diabetes Metab Syndr Obes. 2020 Nov 26;13:4609-4620. doi: 10.2147/DMSO.S282926. PMID: 33273836; PMCID: PMC7705266.
5. Deng N, Zhang X, Zhao F, et al. Prevalence of lipohypertrophy in insulin-treated diabetes patients: a systematic review and meta-analysis. J Diabetes Investig. 2018;9(3):536–543. doi: 10.1111/jdi.12742
6. Hauner H, Stockamp B, Haastert B. Prevalence of lipohypertrophy in insulin-treated diabetic patients and predisposing factors. Exp Clin Endocrinol Diabetes. 2009;104(2):106–110. doi: 10.1055/s-0029-1211431
7. Hajheydari Z, Kashi Z, Akha O, et al. Frequency of lipodysdrophy induced by recombinant human insulin. Eur Rev Med Pharmacol. 2011;15(10):1196–1201.
8. Baruah MP, Kalra S, Bose S, et al. An audit of insulin usage and insulin injection practices in a large Indian cohort. Indian J Endocrinol Metab. 2017;21(3):443–452. doi: 10.4103/ijem.IJEM_548_16
9. Hirsch L, Byron K, Gibney M. Intramuscular risk at insulin injection sites—measurement of the distance from skin to muscle and rationale for shorter-length needles for subcutaneous insulin therapy. Diabetes Technol Ther. 2014;16(12):867–873. doi: 10.1089/dia.2014.0111
10. Kumar D, Miller LV, Mehtalia SD. Use of dexamethasone in treatment of insulin lipoatrophy. Diabetes. 1977;26(4):296–299. doi: 10.2337/diab.26.4.296
11. 35. Phua E-J, Lopez X, Ramus J, et al. Cromolyn sodium for insulin-induced lipoatrophy: old drug, new use. Diabetes Care. 2013;36(12):e204–e205. doi: 10.2337/dc13-1123

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