Increased glucose effectiveness in normoglycemic but insulin-resistant relatives of patients with non-insulin-dependent diabetes mellitus. A novel compensatory mechanism.

Abstract

20 normoglycemic first degree relatives of non-insulin-dependent diabetes mellitus (NIDDM) patients were compared with 20 matched subjects without any family history of diabetes using the intravenous glucose tolerance test with minimal model analysis of glucose disappearance and insulin kinetics. Intravenous glucose tolerance index (Kg) was similar in both groups (1.60±0.14 vs 1.59±0.18, x 10-2 minm-, NS). However, insulin sensitivity (Si) was reduced (3.49±0.43 vs 4.80±0.61, x 10-4 mind per mU/liter, P = 0.05), whereas glucose effectiveness (Sg) was increased (1.93±0.14 vs 1.52±0.16, X 10-2 min-, P < 0.05) in the relatives. Despite insulin resistance neither fasting plasma insulin concentration (7.63±0.48 vs 6.88±0.45, mU/liter, NS) nor first phase insulin responsiveness (Phil) (3.56±0.53 vs 4.13±0.62, mU/liter min' per mg/dl, NS) were increased in the relatives. Phil was reduced for the degree of insulin resistance in the relatives so that the Phil x Si index was lower in the relatives (11.5±2.2 vs 16.7±2.0, x 10-4 min 2 per mg/dl, P < 0.05). Importantly, glucose effectiveness correlated with Kg and with basal glucose oxidation but not with total glucose transporter 4 (GLUT4) content in a basal muscle biopsy. In conclusion we confirm the presence of insulin resistance in first degree relatives of NIDDM patients. However, insulin secretion was altered and reduced for the degree of insulin resistance in the relatives, whereas glucose effectiveness was increased. We hypothesize that increased glucose effectiveness maintains glucose tolerance

Multiple metabolic abnormalities in normal glucose tolerant relatives of NIDDM families

“…Second, C-peptide levels in the fasting and glucose stimulated states were decreased in the relatives indicating impaired insulin secretion. Thus, we have found evidence for both decreased insulin action and decreased insulin secretion in the normal glucose tolerant relatives that supports the observations of other recent studies [20][21][22].…”

“…One previously suggested mechanism involves a compensatory increase in glucose-mediated glucose disposal as determined using the frequent sampled intravenous glucose tolerance test (IVGTT) [21]. Our observations lead us to propose a second complimentary mechanism whereby peripheral insulin levels are maintained through a decrease in hepatic insulin clearance.…”

“…Although the HOMA index provides an indirect assessment of insulin sensitivity, it has been shown to be closely correlated (r = 0.88, p < 0.0001) with the index of insulin sensitivity (M value) derived from the hyperinsulinaemic euglycaemic clamp [29]. Other studies have reported insulin resistance in normal glucose tolerant relatives of NIDDM families [15][16][17][18][19][20][21][22], although the biochemical mechanisms remain to be fully defined. Decreased insulinstimulated glycogen deposition in skeletal muscle appears to be a key abnormality [16,19], while physical fitness, an important determinant of insulin sensitivity in normal man [30], has recently been reported to be decreased in a comparable group of normal glucose tolerant relatives [22].…”

“…insulin resistance is the primary abnormality [14][15][16][17][18][19], while three studies have reported evidence for both impaired insulin secretion and action in normal glucose tolerant relatives [20][21][22]. A number of factors might account for these divergent observations, and include differences in study populations, for example in ethnicity, and methodological differences.…”

“…A number of factors might account for these divergent observations, and include differences in study populations, for example in ethnicity, and methodological differences. Certainly, insulin resistance appears to be of fundamental importance in the Mexican-American [18] and Pima Indian populations [23], while evidence of decreased insulin secretion has tended to come from studies of Caucasians [9][10][11][12][13][20][21][22].…”