In Situ Evidence That Peripheral Insulin Resistance in Adolescents with Poorly Controlled Type 1 Diabetes Is Associated with Impaired Suppression of Lipolysis: A Microdialysis Study

Abstract

This study was undertaken to examine whether insulin resistance in adolescents with poorly controlled type 1 diabetes mellitus (T1DM) is associated with the failure of insulin to suppress lipolysis in adipose and muscle tissues. Using microdialysis techniques, extracellular fluid concentrations of glycerol was measured in adipose and muscle tissue 3 h before and 3 h during a 0.8 mU · kg Ϫ1 · min Ϫ1 · euglycemic clamp. Ten adolescents with poorly controlled T1DM (HbA 1c 10.2 Ϯ 0.2%) were compared with six healthy lean adolescent control subjects. Despite similar increases in plasma insulin in both groups, diabetic subjects exhibited a 39% reduction in peripheral glucose uptake compared with controls (p Ͻ 0.05). In contrast, hepatic glucose production was fully suppressed by insulin in diabetic subjects. At the end of the clamp, extracellular glycerol concentrations were significantly elevated in subjects with diabetes (muscle: 85 Ϯ 7 M for diabetics and 51 Ϯ 8 M for controls, p Ͻ 0.01; adipose: 149 Ϯ 23 M for T1DM and 82 Ϯ 11 M for controls, p Ͻ 0.05), indicating impaired in situ suppression of lipolysis in patients with diabetes. With all subjects considered, the rate of insulin-stimulated metabolism was inversely correlated to glycerol concentration in both adipose (r ϭ Ϫ0.63, p Ͻ 0.01) and muscle (r ϭ Ϫ0.63, p Ͻ 0.01). Our data suggest that failure of insulin to inhibit lipolysis in muscle and adipose tissue contributes to the severe peripheral insulin resistance that characterizes poorly controlled T1DM during adolescence. Type 1 diabetes mellitus (T1DM) in adolescents is a disease in which end organ resistance to insulin and deficiency of the hormone coexist (1). During normal puberty, responsiveness to insulin declines and this physiologic insulin resistance is exaggerated by poorly controlled diabetes (1-3). Compared with healthy lean preadolescents, healthy lean adolescents show a selective defect in insulin's ability to stimulate nonoxidative glucose disposal in peripheral (muscle and adipose) tissues; insulin-mediated increases in peripheral glucose oxidation are unaffected by normal puberty (4, 5). In contrast, the exaggerated insulin resistance in adolescents with poorly controlled T1DM involves defects in insulin's ability to stimulate both oxidative and nonoxidative glucose metabolism (5).An implication of the much debated glucose fatty-acid cycle (Randle cycle) is that increased FFA availability interferes with muscle glucose metabolism and contributes to the cause of many insulin-resistant states, including adolescence and T1DM (6 -8). Using the insulin clamp technique and indirect calorimetry, we have shown that severely insulin-resistant adolescents with poorly controlled T1DM fail to suppress circulating FFA levels or rates of fat oxidation in comparison with healthy adolescent controls in response to insulin levels similar to those achieved postprandially by healthy adolescents (5). The wholebody methods used in that study, however, did not allow us to distinguish the relative contributions of...

Nonobese, insulin-deficient Ins2Akitamice develop type 2 diabetes phenotypes including insulin resistance and cardiac remodeling

“…Moreover, insulin-mediated inhibition of adipocyte lipolysis may be blunted in Ins2 Akita mice, since plasma lipid levels were not significantly altered between basal and insulin clamp state. This observation is consistent with previous findings indicating impaired suppression of lipolysis in poorly controlled type 1 diabetic subjects (11). Despite blunted insulin action on lipolysis, insulin-stimulated glucose uptake in white adipose tissue was increased in Ins2 Akita mice.…”

“…The latter event may be due to lipid-mediated activation of PKC, as observed in rodents, which increases serine phosphorylation of IRS-1 and causes insulin resistance in skeletal muscle (3). Insulin resistance also develops in subjects with type 1 diabetes and lean type 2 diabetic subjects, but the underlying mechanism remains unresolved (11,14,32,45). Marked increases in intramyocellular lipid content are observed in type 1 diabetic subjects who develop insulin resistance in skeletal muscle (32).…”

Insulin resistance in type 1 diabetes: what is ‘double diabetes’ and what are the risks?

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Targeting caveolin-3 for the treatment of diabetic cardiomyopathy

“…As a consequence, the heart relies on FFA as an alternative energy source, increasing FFA uptake and utilisation ( Avogaro, et al, 1990;Doria, et al, 1991;Herrero, et al, 2006). This dependence on FFA utilisation may be further exacerbated by increased levels of systemic FFA, due to increased lipolysis in the absence of insulin inhibition (Heptulla, et al, 2003). However, it must be noted that insulin treatment has been shown to restore short-term cardiac metabolism (Avogaro, et al, 1990).…”