The prevalence of diabetes mellitus (DM) is 830 million worldwide in 2022, which is 14% of the adults aged 18 and older. It is quite high when compared to 200 million of the adults affected with DM in 1990 according to WHO [1]. This increase in prevalence in DM can also show a probable continuation in surge in atypical complications like Diabetic Myonecrosis (DMN), as 116 cases diagnosed in 2003 has risen to 200 in 2015 [2­­,3]. The earliest description of DMN was given by Angervall and Sterner in 1965 [4]. He described as tumoriform focal degeneration. Other descriptions include spontaneous diabetic muscle infarction, aseptic myonecrosis, and ischemic myonecrosis. DMN occurs as a result of long standing, poorly controlled diabetes. It is described in both in Type 1 DM(T1DM) and type 2 DM(T2DM) with age of presentation at 42.6–44.5 years [5]. DMN is reportedly more common in T1DM with higher incidence in females [6]. The mean duration of DM with muscle infarction was 18.9 years in T1DM and 11 years in T2DM [5]. Studies show an average HbA1c of 9.3% at the time of diagnosis of DMN with the presence of coexisting micro- and macro-vascular complications in diabetic patients due to persistently elevated blood sugars, to be present, such as congestive heart failure, renal failure (diabetic nephropathy, end stage renal disease on dialysis), hypertension, atherosclerotic diseases, peripheral vascular diseases, diabetic neuropathy, and retinopathy [7–9].

The occurrence of DMN is seen to be more frequent in T1DM and in women [6,10]. The pathogenesis although unknown, suggests a vascular origin likely because of nonenzymatic glycosylation of proteins in the walls of microvasculature resulting in ischaemia, and a further trigger of an inflammatory cascade producing ischaemic necrosis. Subsequent reperfusion generates reactive oxygen species and inflammatory cytokines causing further damage to the vasculature [11]. This hypothesis is supplemented by the commonly seen presence of microvascular complications, specifically, advanced diabetic retinopathy and renal disease. However, there have been cases of DMN in patients without vascular complications of diabetes, one such case report being that of a woman with T1DM without any micro- and macro-vascular complications of DM, although she presented with long standing altercating hyper- and hypo-glycaemia from several years [12]. The pathogenesis suspected here is elevated HIF-alpha and Rac-1 expression during hyperglycaemia, producing a state of pseudohypoxia, and hypoglycaemia (due to probable insulin overdose) producing hypophosphatemia and resultant rhabdomyolysis secondary to hypophosphatemia; all in all, causing muscle infarction in this case [13–15].

Patients presents with acute pain and swelling which is non-traumatic origin of the affected muscle group. It usually affects lower limbs especially anterior thigh region and is unilateral. The typical clinical manifestations include acute severe localised pain out of proportion to the physical signs and rapidly progressive over days in the affected muscles with localised swelling and induration. Pain is continuous, exacerbated by movement and also present at rest. Local examination reveals tenderness, warmth, and induration. Ambulation is difficult due to pain when lower extremities is involved. Examination of adjacent joints may be normal with normal range of motion without neurological deficits at the site of involvement. Quadriceps is commonly affected muscle with an incidence rate of 62%. With decreasing in frequency DMN affects hip adductors (13%), hamstrings (8%) and hip flexors (2%) [5,6,16], however any muscle group can be affected. Upper limb involvement is rarely described. Bilateral occurrence simultaneously is seen in 10% of patients [17,18]. Recurrence rate may be up to 34.9% usually involving contra-lateral limb within 6 months [6,19]. Recurrence in the same or opposite limb is in about 50% of the cases over a period of time. Systemic signs of infection such as fever is absent in majority. Rarely if the extent of infarction is severe enough to affect adjacent nerves such as DMN of the hand with resultant Acute Carpal Tunnel Syndrome causing both sensory and motor deficits on examination [20]. Bilateral reflexes will be symmetrical and normal as well as bilateral pulses of extremities involved will be normal and palpable. Most cases show no history of recent trauma, surgery, muscular injections/drug use or recent travel that helps physicians to rule out differentials such as compartment syndrome post trauma or post-surgical infections, probable abscess formation due to intra-muscular injections or other infectious aetiology. Deep venous thrombosis, pyomyositis, soft tissue abscess, necrotizing fasciitis, dermatomyositis, proliferative myositis, focal myositis/nodular myositis, primary lymphoma of muscle, benign tumours or sarcomas of the muscle, diabetic amyotrophy, osteomyelitis, exertional muscle rupture, and ruptured Baker’s cyst are commonly considered differential for DMN [6,21]. In patients with chronic renal disease, calciphylaxis also needs to be considered [22].

Routine investigations include complete blood count, with most cases showing a normal Haemoglobin, white blood cell count, platelets, and biochemical parameters in majority of the cases. Some show non-specific elevation in total count, serum creatinine kinase, C-reactive protein, Serum. Lactate Dehydrogenase, and ESR. Elevated ESR, CRP, and creatinine phosphokinase is not directly proportional to the severity of myonecrosis, thus delaying the diagnosis. Serum osmolarity, with presence or absence of acidosis should be checked for, as ketosis as a causation for myopathy must be ruled out. Serum electrolytes including serum phosphate and serum calcium should be done, as dys-electrolytemia common in hyperglycaemic states, is a differential to be considered. Iron profile, thyroid profile, liver functions including enzymes (aspartate and alanine transaminases, glutamyl transferases), coagulation profile, serum cortisol and lipid profile must be sent for, to rule out other probable causes for myopathy. Infectious profile including Trichinella, Taenia solium, Toxoplasma, CMV, HIV-1/2, HTLV-1/2 must also be evaluated for. Micro and macrovascular complications of DM should be evaluated simultaneously.

Ultrasound can be initial non-invasive imaging modality that can be used to rule out abscess, DVT, or subcutaneous edema. Venous and arterial doppler should always be done to rule out DVT and peripheral arterial disease. DMN on ultrasound appears as a well marginated hypoechoic intramuscular lesion. The additional sonographic features include: Internal linear structures that are compatible with muscle fibres coursing through the lesion; the lack of a predominantly anechoic region; and an absence of motion or swirling of fluid with transducer pressure [23]. Predominantly anechoic areas are seldom seen. Posterior acoustic enhancement may be seen if the lesions are not in close proximity to the bone cortex. Doppler study may not demonstrate increased flow in the lesions. CT of the involved muscle may not give much additional information but contrast enhanced CT may show low attenuation lesions with ring enhancing margins localized to group of muscles involved [23].

Magnetic resonance imaging (MRI) is a very effective diagnostic tool to diagnose DMN (Figures 1 and 2 represents typical findings). MRI, with IV Gadolinium as contrast is the choice for imaging. It shows well defined regions with iso to low signal intensity on T1-weighted images and predominantly high signal intensity on T2 weighted STIR or Proton density weighted with fat saturation images [6,19,24-26]. Subcutaneous edema, Subfascial hyperintensity and fluid are present in majority. Administration of IV contrast demonstrates peripheral rim enhancement in the affected regions. Biopsy is the gold standard, although it is not considered routinely due to its invasiveness and several negative effects such as delayed tissue healing, hematoma formation, and superimposed infections in diabetic patients with poorly controlled sugar levels [27]. When performed, it reveals necrosis, edema, lymphocytic infiltration, and thrombosis of microvasculature and surrounding areas of fibrosis [28]. The necrotic muscle is replaced with fibrous tissue followed by lymphocytic infiltration and muscle regeneration in later stages. It is considered when the levels of suspicion of DMN are very low and other diagnostic and empirical therapeutic interventions have failed to alleviate the condition. However, with the MRI findings, infectious myositis or pyomyositis, necrotizing fasciitis, or focal inflammatory myositis must continue to be kept in mind [29]. Focal inflammatory myositis can be ruled out with a negative screen for anti-nuclear antibodies, ANCA, anti-DNA abs, anti-smooth muscle abs, and anti-phospholipid abs.

One of the earliest reviews by Trujillo et al. included 115 patients with 166 episodes from 47 references from the literature [6]. Fifty-nine percent had T1DM with mean age at the time of presentation was 42.6 years of which and mean duration of diabetes was 14.3 years. Micro-vascular complications of diabetes like nephropathy (71.1%), retinopathy (56.6%), and neuropathy (54.5%) were also present. In this series also DMN most frequently affected the thigh (83.7%). Quadriceps muscles were the most commonly affected of which vastus lateralis (24%) and the vastus medialis (22%) were most frequently affected. While the calf involvement was reported in 32 cases (19.28%) and bilateral in 14 cases (8.4%). Only one case involving upper limb (forearm) was reported.

Horton et al. did a recent systemic review of 126 cases of DMN from 87 articles [3]. The mean age of presentation was 44.6 years (20–67) and it was 35.9 years for T1DM and 52.2 for T2DM. The mean DM duration at diagnosis was 18.9 (5–33) years for T1DM and 11.0 (1–25) years for T2DM. The mean HbA1c in 51 cases was 9.34% (5–21). Of the 126 cases, 117 had other vascular complications with most common was nephropathy which was present in 75% of cases. Fifty-five cases (46.6%) had concurrent retinopathy, nephropathy, and neuropathy. Thigh pain/swelling was most commonly reported presenting symptom in 79 cases (71.2%), Calf pain/swelling and upper arm pain/swelling were noted in 17 (15.3%) and in six (5.4%) cases respectively. Thirty-four point nine percent of recurrence were noted amounting to 44 episodes of which 61.4% were noted at different location/muscle group other than the initial presentation.

Yong et al. systematically reviewed the cases of DMN in end stage renal disease [22]. Forty-one patients of CKD were included which were described in 24 articles. The mean age at presentation was 44.2 years and 22 were women (53.7%). T2DM was present in 53.7% of patients. Of the 41 patients, 60.1% were on hemodialysis, 21% on peritoneal dialysis, and 12.2% had renal transplantation. The proximal lower limb musculature was the most commonly affected site with muscle pain and swelling being the most frequent manifestation. Sixteen cases (39.0%) underwent muscle biopsy. More than 60% had HbA1c of greater than 7.

Meher et al. described six cases of DMN of which four patients were women [23]. The mean age at presentation was 51.5 ± 7.2 years (range 37–56 years) All patients had T2DM with mean duration of diabetes of 10.16 ± 8.23 years (range 1–25 years). Neuropathy and dyslipidaemia were present in all cases. Nephropathy was present in five cases, and retinopathy in four cases. All six patients had involvement of the quadriceps, and one had additional calf muscle involvement. One each had bilateral involvement and recurrence in the opposite thigh after 2 years initial presentation.

Nalloor et al. described seven episodes in six patients. They had a median age of 55 years (range 43 – 71 years) [30]. All had T2DM with median duration of 10 years (range 10–20 years). The median HbA1c was 7.3 (6.3-8.8%). They presented with acute, non-traumatic pain with swelling affecting the thigh region. Microvascular complications in the form of either retinopathy, nephropathy, and/or neuropathy were noted in all patients. Creatinine and ESR levels were raised in all 7 cases. Five of them were known cases of chronic kidney disease and another 2 were newly detected. Recurrence was present in 1 patient in the contra-lateral limb within a year of first episode. None of them had upper limb involvement. All cases were treated conservatively with bed rest, analgesics, glycemic control, diuretics with supportive measures without any surgical intervention. Two weeks was the mean time taken for recovery.

Diabetic myonecrosis is a self-limiting condition that resolves spontaneously over a period of time usually 2-4 weeks in most of the cases. Patients should be treated conservatively along with supportive care with good glycemic control. NSAIDs such as aspirin can be used for pain relief. As the possible explanation for DMN is microvascular pathogenesis, anti-platelet therapy is theoretically feasible [31]. Kapur’s three treatment strategy is supportive (bed rest, analgesics), medical (anti-platelet therapy, steroids), and surgical treatment may be options [32]. The meantime recovery for the 3 strategies were 5.5, 8.1, and 13 weeks, making surgery an unfavourable modality [32]. Hence, the study by Kapur et al. also concluded excisional biopsy, early debridement, mobility, to all have led to complications and delayed recovery. Thus, the leading treatment is simply supportive. Surgical intervention must be limited if the condition is complicated with abscess formation or peripheral arterial compromise. Although DMN has a good short-term prognosis, there is a high chance of recurrence either in the same limb or the other. The likelihood of recurrence in the same muscle or contralateral limb is greater than 50%, with as many as 1 to 2 episodes per year after the initial event. Long term survival in patients who are known to have micro/macrovascular complications is usually poor.

Sirtuins are a family of conserved, NAD+-dependent protein deacetylases that play a role in various biological processes. Their involvement in various cellular processes include metabolism, stress resistance, genomic stability, DNA repair, aging, and disease. In the context of skeletal muscle, their roles have gained considerable attention owing to involvement in metabolic regulation, developmental processes, and implications in numerous muscular disorders. Mammals have seven sirtuin isoforms, SIRT1–7, each with unique functions and subcellular localization. Sirtuins, especially SIRT1, play a role in maintaining cellular homeostasis and are implicated in various diabetic complications. Studies have shown that SIRT1 is often downregulated in diabetic conditions, and its activity is reduced in diabetic nephropathy. It has also been linked to the prevention of muscle loss and the maintenance of muscle function during aging. Sirtuins, especially SIRT1, are involved in regulating glucose uptake, fatty acid oxidation, and mitochondrial dynamics within skeletal muscle. 

Measuring plasma SIRT1 levels in patients with diabetic myonecrosis is crucial for several reasons: it can help in early diagnosis and management of the condition, predict the progression of the disease, and potentially guide treatment strategies to prevent muscle necrosis and reduce the risk of metabolic complications. Measuring plasma SIRT1 levels in patients with diabetic myonecrosis can provide insights into the pathogenesis of the disease and help in early diagnosis and management. It may also guide to strategize the treatment to prevent muscle necrosis and reduce the metabolic complications.

DMN has a good short time prognosis with recovery in many cases within 3-4 weeks, albeit physicians must keep alert to identify this under-diagnosed condition at the earliest to prevent morbidity. Given its rarity, our knowledge of pathogenesis and causes of DMN and so the optimal treatment for it, remains unclear to this date, and therefore further studies are essential, to enhance our understanding of this uncommon complication of diabetes. The specific role of sirtuins in diabetic myonecrosis is not well-established. It needs further studies to look into metabolic complications of diabetes including micro/macrovascular complications and skeletal muscles.