Age-Dependent Onset of Insulin Resistance in Insulin-Resistant Mice

Abstract

We have previously isolated spontaneous insulin-resistant mice (ddY-H) and non-insulin-resistant mice (ddY-L) from ddY mice. In the present study, age-dependent onset of insulin resistance in obese ddY-H mice was investigated by comparing with lean ddY-L mice. In ddY-H mice fed a standard diet, an increase in elevation of glucose-stimulated plasma insulin level, glucose intolerance in an intraperitoneal glucose tolerance test, and a reduction of hypoglycemic action of insulin were found at 9 weeks of age, but not at 6 weeks of age. When ddY-H mice were administered nateglinide, a greater elevation of plasma insulin level and a less decrease of serum glucose level were observed at 9 weeks of age. These changes developed progressively with age. These findings suggest that insulin resistance is induced at 9 weeks of age. The age-related change in insulin resistance was correlated with reductions in mRNA expression and protein content of the insulin receptor (InsR), and insulin receptor substrate (IRS)-1 and IRS-2 in the epididymal adipose tissue. On the other hand, in the liver, mRNA expression of InsR and IRS-1 did not change at any age, although that of the IRS-2 was reduced. Thus, in ddY-H mice, insulin resistance and glucose-stimulated hyper-secretion of insulin are induced at 9 weeks of age and are reciprocally affected, resulting in progression to a more severe state at an older age. Insulin resistance may be attributed, at least in part, to the decreases in the mRNA expressions and proteins of InsR, IRS-1 and IRS-2 in adipose tissue. Key words insulin resistance; age-related onset; insulin secretion; insulin receptor Type 2 diabetes mellitus is a complex disease characterized by hyperglycemia resulting from impaired pancreatic β-cell function and a decreased action of insulin on target tissues.

Ageing influences the relationship of circulating miR-33a and miR-33b levels with insulin resistance and adiposity

“…This fact is an important remark because we show that age adds at some point to the presentation or maintenance of IR; in this regard, the contribution of age to the development and establishment of the pathogenic process of IR was demonstrated by the experiments of Facchini et al 31 and Ide et al, 32 in which they showed that mice exposed to hypersecretion of insulin stimulated by glucose develop IR at 9 weeks of age, but not before and it is exacerbated at 15 weeks of age.…”

Aged garlic extract ameliorates fatty liver and insulin resistance and improves the gut microbiota profile in a mouse model of insulin resistance

“…During the progression of diabetes, pancreatic β cells adapt their secretory capacity to compensate the elevated glycemia and the peripheral insulin resistance and, as a result, the serum insulin level becomes elevated (48). We have previously shown that insulin resistance in ddY-H mice is induced at 9 weeks of age and develops progressively with age (37)(38)40). The age-dependent onset of insulin resistance was closely related to the increase of serum insulin level.…”

“…The age-dependent onset of insulin resistance was closely related to the increase of serum insulin level. The elevation of the serum insulin level was temporally associated with the decrease in mRNA expression and proteins of insulin receptor (IR), IRS-1 and IRS-2 in adipose tissue of ddY-H mice (40). Therefore, together with glucose intolerance, the elevation of serum insulin levels in ddY-H mice indicates an induction of insulin resistance.…”

“…We previously succeeded in isolating and breeding spontaneous insulin-resistant mice and healthy control mice, termed ddY-H and ddY-L mice, respectively (37). In ddY-H mice, hepatic steatosis with obesity, insulin resistance, hyperglycemia and altered adipokine profiles are observed even when the mice are fed a standard diet containing 13% energy from fat and 61% carbohydrates, but not so in ddY-L mice (37)(38)(39)(40). The prevailing hypothesis is that hepatic steatosis develops as a result of the increased absorption of fat from the intestines and the increased uptake of fatty acids into hepatic cells via the increased expression of peroxisome proliferator-activated receptor γ (PPARγ) (39).…”

“…The prevailing hypothesis is that hepatic steatosis develops as a result of the increased absorption of fat from the intestines and the increased uptake of fatty acids into hepatic cells via the increased expression of peroxisome proliferator-activated receptor γ (PPARγ) (39). The age-dependent onset of insulin resistance with hyperinsulinemia in ddY-H mice may be attributed to the decreases in the mRNA expression and proteins of insulin receptor, insulin receptor substrate (IRS)-1 and IRS-2 in adipose tissue (40).…”