Insulin secretion, insulin action, and hepatic glucose production in identical twins discordant for non-insulin-dependent diabetes mellitus.

Abstract

12 identical twin pairs discordant for non-insulin-dependent diabetes mellitus (NIDDM) were studied for insulin sensitivity (euglycemic insulin clamp, 40 mU/m2 per min), hepatic glucose production (HGP, [3-3H] glucose infusion), and insulin secretion (oral glucose tolerance test and hyperglycemic [12 mM] clamp, including glucagon administration). Five of the nondiabetic twins had normal and seven had impaired glucose tolerance. 13 matched, healthy subjects without a family history of diabetes were included as control subjects. The NIDDM twins were more obese compared with their non-diabetic co-twins. The nondiabetic twins were insulin resistant and had a delayed insulin and C-peptide response during oral glucose tolerance tests compared with controls. Furthermore, the nondiabetic twins had a decreased first-phase insulin response and a decreased maximal insulin secretion capacity during hyperglycemic clamping and intravenous glucagon administration. Nondiabetic twins and controls had similar rates of HGP. Compared with both nondiabetic twins and controls, the NIDDM twins had an elevated basal rate of HGP, a further decreased insulin sensitivity, and a further impaired insulin secretion pattern as determined by all tests. In conclusion, defects of both in vivo insulin secretion and insulin action are present in non-and possibly prediabetic twins who possess the necessary NIDDM susceptibility genes. However, all defects of both insulin secretion and glucose metabolism are expressed quantitatively more severely in their identical co-twins with overt NIDDM. (J. Clin. Invest. 1995. 95:690-698.)

Role of insulin resistance in the pathogenesis of NIDDM

“…Third, even in this study abdominal fat mass and VO2max were not determined. This may, however, be of lesser concern than in the previous studies [15,84,85] since a large number of subjects was studied and no difference in insulin sensitivity was found. On one occasion, saline (NaC1) was infused, on the other 10 % glucose was infused to increase plasma glucose to -17 mmol/1.…”

“…This would seem important particularly when a small number of subjects is studied, to H. Yki-Jfirvinen: Insulin resistance and NIDDM accurately control for known causes of variation in insulin action, and to avoid recruitment bias. Furthermore, in the study in which identical twins discordant for NIDDM were studied, an insulin secretory defect and normal insulin sensitivity was found in twins with normal glucose tolerance [84]. Insulin sensitivity was impaired only in the twins with impaired glucose tolerance [84].…”

“…It has recently been proposed, in cross-sectional studies, that individuals with a positive family history for NIDDM are more insulin resistant than those with a negative family history, and that insulin resistance may be genetically determined in such individuals [15,[83][84][85]. Some potential shortcomings of these studies should be considered before pursuing the hypothesis that insulin resistance is the primary abnormality predisposing to NIDDM.…”

“…Furthermore, in the study in which identical twins discordant for NIDDM were studied, an insulin secretory defect and normal insulin sensitivity was found in twins with normal glucose tolerance [84]. Insulin sensitivity was impaired only in the twins with impaired glucose tolerance [84]. In a recent study by Banerji et al [49], where intra-abdominal fat mass was determined using CT scanning in normoglycaemic black NIDDM men, whole body insulin sensitivity was strongly inversely (r = -0.81) related to intra-abdominal fat (Fig.…”

Beta-cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study

“…Rather, they are based on the empiric observation that individuals with a 2-h PG between 7.8 and 11.0 mmol/l have an increased risk of developing T2DM later in life compared to individuals with a 2-h PG less than 7.8 mmol/l [24]. Insulin resistance has been shown to be present in the first-degree relatives of T2DM individuals before the onset of IGT [1,10,11,12,13,45,46,47,48] at a time when glucose tolerance is normal. This observation, taken in concert with the present findings concerning beta-cell dysfunction in individuals with NGT, underscores the arbitrariness of current IGT criteria, since the two major pathophysiological disturbances-insulin resistance and beta-cell dysfunction-are already well established in individuals with "normal" glucose tolerance.…”