insulin detemir has now become established as an effective basal insulin preparation and is widely used in the management of both type 1 and type 2 diabetes . although it is similar in efficacy to isophane insulin , we have observed a relative lack of efficacy in two patients with significant hypertriglyceridemia and established nonalcoholic fatty liver disease , suggesting that there are circumstances where the efficacy of detemir may be adversely affected by specific metabolic parameters . patient 1 was a 56yearold caucasian man with a 4year history of poorly controlled type 2 diabetes and marked hypertriglyceridemia ( random triglycerides were 28.7 mmol / l and total cholesterol was 7.9 his mother had type 2 diabetes , but there was no other family history of note . he denied alcohol consumption for the previous 14 years and had been only a light drinker previously . at the time of starting insulin he was being treated with metformin , gliclazide , fenofibrate , and omacor . on examination , he was obese with a body weight of 109 kg and bmi of 32 kg / m . glycated hemoglobin ( hba1c ) was 69 mmol / mol ( 8.5% ) , fasting triglycerides 8.4 mmol / l , and total cholesterol 4.5 mmol / l . mol / l ( egfr 102 ml / min/1.73 m ) and liver enzymes were slightly elevated : ast 71 serum albumin was normal 47 g / dl ( 3550 ) , inr 1.04 , and hepatitis serology was negative . ultrasound confirmed a 17.7cm spleen and ct demonstrated nonalcoholic fatty liver disease ( nafld ) . in view of splenomegaly , he underwent a bone marrow aspirate and trephine biopsy , both of which were normal . a liver biopsy confirmed hepatosteatosis with marked steatosis , mild inflammatory activity , and hepatocellular ballooning ( fig . 1a ) . in part of the biopsy , bridging fibrosis with parenchymal nodule formation was in keeping with cirrhotic transformation ( fig . ( b ) reticulin stain ( gordon and sweet ) reveals , in part of the biopsy core , bridging fibrosis with parenchymal nodule formation in keeping with cirrhotic transformation . insulin detemir ( 14 units nocte ) was commenced as his random glucose values were 1722 mmol / l . he was using 158 units per day of detemir , in divided doses , plus insulin aspart 24 units with each meal . despite these doses , mmol / l and hba1c remained unsatisfactory at 69 mmol / mol ( 8.5% ) . basal insulin was then changed to insulatard 70 units per day in divided doses ( insulin aspart dose unchanged ) and within four months his hba1c had fallen to 51 mmol / mol ( 6.8% ) and by 12 months he had lost 6 kg of weight . patient 2 was a 68yearold man with a 20year history of type 2 diabetes and type v hyperlipidemia . for two years , after the diagnosis of diabetes , he was managed with oral hypoglycemic agents alone . he then developed necrotizing pancreatitis ( considered secondary to hypertriglyceridemia ) and was treated with human isophane insulin and human soluble insulin for ten years before being switched to detemir and novorapid . he was referred due to the patient 's concern of escalating insulin dose and associated weight gain of 20 kg over the previous five years . at the time of referral the detemir dose was 120 units twice daily and novorapid 120 units with each meal ( total of 600 units / day ) . he did not drink alcohol . on examination he was obese with body weight of 126 kg and bmi of 44.6 kg / m . random triglycerides were markedly elevated ( 31.9 mmol / l ) , total cholesterol was 6.3 mmol / l , and hdl was 0.3 there was no clinical or biochemical evidence of any endocrinopathy to explain insulin resistance and no evidence of immunemediated insulin resistance . liver enzymes and synthetic function were normal but there was mild renal impairment ( serum creatinine 145 mol / l ; egfr 77ml / min/1.73 m ) . detemir was changed to isophane insulin 100 units bd and novorapid reduced to 100 units / meal . after six months , the dose of insulatard had stabilized at 140 units bd and novorapid 50 units tds ( 430 units / day  30% reduction in total daily dose ) , his weight remained unchanged and despite the reduction in insulin dose , hba1c improved to 50 mmol / mol ( 6.7% ) . the two cases presented in this report showed that in patients with a history of severe hypertriglyceridemia and significant fat infiltration of the liver , a hepatoselective insulin ( detemir ) appeared less efficacious in achieving glycemic control . insulin detemir differs from human insulin by the deletion of the amino acid threonine in position 30 of the b chain , plus the addition of a c14 fatty acid chain at position 29 of the b chain . this allows detemir to reversibly bind to serum albumin 1 and is a characteristic that has led to it being considered a hepatoselective insulin : the albumin  insulin molecule is unable to pass through the capillary endothelial cell barrier to reach peripheral adipocytes , whereas in the liver , the albumin  detemir molecule is able to pass freely through the sinusoids . this allows it to exert a greater effect on hepatocytes than in peripheral tissues 2 . hypothetically , the efficacy of hepatoselective insulin may be reduced in nafld by less hepatic exposure to insulin ( due to increased insulin clearance or to portosystemic shunting ) , or from direct hepatic parenchymal cell damage . given that the usual action of insulin is to stimulate the liver to store glucose in the form of glycogen and to switch off gluconeogenesis , underexposure of hepatocytes to insulin would lead to hyperglycemia . a portosystemic shunt was thought to be unlikely in these patients as there were no radiological features of collateral ( variceal ) circulation . increased clearance of detemir might have occurred ; premarketing studies suggested that hepatic impairment affected the bioavailability of insulin . in these studies there was a 3547% faster clearance of detemir in patients with severe / moderate liver insufficiency as compared to healthy subjects 3 . by contrast , clearance of human insulin is usually reduced in liver failure 4 and insulin clamp studies with human insulin have shown decreased clearance in patients with fat infiltration of the liver 5 . in a mouse model of nafld ( induced by highfat feeding ) , there was decreased insulin activation of glycogen synthase and increased gluconeogenesis 6 during a euglycemic  hyperinsulinemic clamp , suggesting a direct , adverse consequence of hepatic fat accumulation . the closest model available is of detemir 's action in obesity where the presence of nafld may be inferred 7 . a pharmacodynamic study of 18 subjects showed that in the presence of grade 1 obesity ( bmi 3035 kg / m ) a lower glucose infusion rate was required to maintain normoglycemia after administration of detemir , compared to neutral protamine hagedorn ( nph ) insulin or glargine 8 . advanced hepatocellular fibrosis may be associated with a change in the configuration of the sinusoidal endothelium , including loss of fenestrations , which would reduce the exchanges between hepatocytes and sinusoidal blood . therefore , this would suggest that in severe nafld / cirrhosis , higher doses of detemir insulin would be required . an alternative hypothesis is that hypertriglyceridemia may have a direct , adverse effect on detemir action . the binding of detemir to albumin could be affected by the lipid content of plasma . competition experiments with fatty acids have shown that levemir can be displaced from human albumin by longchain fatty acids ( containing at least 12 carbon atoms ) but with much weaker competition by a medium chain fatty acid 9 . the significance of this is uncertain , but potentially it could lead to loss of biological activity , or unpredictable release or clearance of levemir . antibody development has been observed in phase 3 clinical trials of detemir , but did not impact on metabolic control 10 . there were no specific features of alternative cause(s ) for a relative lack of efficacy of insulin , such as lysosomal storage disease or monogenic insulin resistance syndromes  and these were not tested for . it is possible that the cases described relate to less common etiologies of insulin resistance . in managing patients with diabetes , interindividual differences in response to insulin may be encountered ; a relative lack of efficacy with one type of insulin may not be seen with an alternative insulin . such a response may be unrelated to the degree of hepatoselectivity of the insulin chosen . in conclusion , these two cases suggest that detemir may be less efficacious in patients with significant hypertriglyceridemia complicated by nafld . it is not possible to determine a precise mechanism to explain this observation but this could be due primarily to hypertriglyceridemia or due to the effects of infiltration of hepatic parenchyma with lipid .
key clinical messageinsulin detemir is commonly used in obese patients with diabetes mellitus as it is considered hepatoselective and causes less weight gain . 
 we describe a relative lack of effectiveness of detemir in patients with significant nafld and hypertriglyceridemia , compared to isophane insulin . 
 this may affect how such patients are managed with insulin .