Disproportionate elevation of immunoreactive proinsulin in Type 2 (non-insulin-dependent) diabetes mellitus and in experimental insulin resistance

Ward, W. Kenneth; LaCava, Edward C; Paquette, Thomas L.; Beard, James C.; Wallum, B. J.; Porte, Daniel

doi:10.1007/bf00296991

Cited by 288 publications

(200 citation statements)

References 13 publications

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“…Elevation of the serum PI/I ratio in diabetic patients has been reported in several studies [4][5][6][7][8]. The relative increase in serum proinsulin concentration is not restricted to Type 2 diabetes.…”

Section: Discussionmentioning

confidence: 88%

“…They are secreted in a small amount together with insulin [3]. It is known that the serum proinsutin/insulin ratio (PI/I ratio) is elevated in patients with Type 2 (non-insulin-dependent) diabetes mellitus compared to healthy subjects [4][5][6][7][8]. It is usually supposed that proinsulin is secreted in a disproportionately greater amount compared with insulin in Type 2 diabetic patients, although the altered metabolism of proinsulin relative to insulin cannot be ruled out.…”

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confidence: 99%

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Hyperinsulinaemia in obesity is not accompanied by an increase in serum proinsulin/insulin ratio in groups of human subjects with and without glucose intolerance

et al. 1991

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Summary. Serum proinsulin is disproportionately elevated compared to insulin in Type2 (non-insulin-dependent) diabetes mellitus. We studied the effect of obesity on serum proinsulin with varying degrees of glucose intolerance. Serum proinsulin and insulin were measured during a 75 g oral glucose tolerance test in 73 obese and 74 non-obese subjects with normal, borderline or diabetic-type glucose tolerance. Proinsulin was assayed by a direct radioimmunoassay using proinsulin-specific antiserum. Fasting serum proinsulin and insulin and the summed values of proinsulin and insulin during oral glucose tolerance test were significantly, or tended to be, higher in obese subjects than in those without obesity in each category of glucose tolerance. However, the molar ratio of proinsulin to insulin was nearly the same between obese and non-obese groups with a similar degree of glucose tolerance. On the other hand, the proinsulin/insulin ratio increased progressively with the deterioration of glucose tolerance. We conclude that proinsulin secretion is disproportionately increased in the presence of glucose intolerance but not by obesity itself. Each Beta cell seems to function normally in obese subjects while glucose tolerance remains normal.

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Section: Discussionmentioning

confidence: 88%

mentioning

confidence: 99%

Hyperinsulinaemia in obesity is not accompanied by an increase in serum proinsulin/insulin ratio in groups of human subjects with and without glucose intolerance

et al. 1991

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“…It is also recognised that elevated circulating proinsulin levels are an important and consistent feature of NIDDM [2][3][4][5], and may represent a specific defect of pancreatic beta-cell function. There is continuing debate as to whether insulin deficiency or insulin resistance represents the primary abnormality which predisposes to the development of NIDDM [6], although it is clear that comparative insulin deficiency is a sine qua non for NIDDM to develop [7].…”

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confidence: 99%

Multiple metabolic abnormalities in normal glucose tolerant relatives of NIDDM families

et al. 1997

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Non-insulin-dependent diabetes mellitus (NIDDM) is a complex metabolic condition characterised by both impaired insulin secretion and insulin resistance [1]. It is also recognised that elevated circulating proinsulin levels are an important and consistent feature of NIDDM [2][3][4][5], and may represent a specific defect of pancreatic beta-cell function. There is continuing debate as to whether insulin deficiency or insulin resistance represents the primary abnormality which predisposes to the development of NIDDM [6], although it is clear that comparative insulin deficiency is a sine qua non for NIDDM to develop [7].In an attempt to identify the early fundamental abnormalities, non-diabetic first degree relatives of NIDDM patients have been studied, as they have a 40 % lifetime risk of progressing to diabetes [8]. However, such an approach has so far failed to clarify matters, as some studies have found a principal defect of insulin secretion [9-13], several have suggested that Diabetologia (1997Diabetologia ( ) 40: 1185Diabetologia ( -1190 Multiple metabolic abnormalities in normal glucose tolerant relatives of NIDDM families Summary Non-diabetic first degree relatives of noninsulin-dependent diabetic (NIDDM) families are at increased risk of developing diabetes mellitus, and have been studied to identify early metabolic abnormalities. Hormone concentrations measured by specific enzyme immunoassays were assessed in non-diabetic relatives of North European extraction, and control subjects with no family history of diabetes were matched for age, sex and ethnicity. A 75-g oral glucose tolerance test was conducted and those with newly diagnosed NIDDM were excluded. Basal insulin resistance was determined by homeostasis model assessment (HOMA), and hepatic insulin clearance by C-peptide:insulin molar ratio. Relatives (n = 150) were heavier (BMI: p < 0.0001) than the control subjects (n = 152), and had an increased prevalence of impaired glucose tolerance (15 vs 3 %, p < 0.01). The relatives had increased fasting proinsulin levels and decreased C-peptide levels following the glucose load, while insulin levels were increased at all time points. To examine whether the differences in hormone levels were secondary to the differences in glucose tolerance and adiposity, we studied 100 normal glucose tolerant relatives and control subjects pairmatched for age, sex, waist-hip ratio and BMI. The differences in proinsulin levels were no longer apparent. However, the relatives remained more insulin resistant, and had decreased C-peptide levels and Cpeptide:insulin ratios at all time points. In conclusion, we have identified several metabolic abnormalities in the normal glucose tolerant relatives, and propose that the decreased hepatic insulin clearance helps to maintain normoglycaemia in the face of combined insulin resistance and decreased insulin secretion. [Diabetologie (1997[Diabetologie ( ) 40: 1185[Diabetologie ( -1190

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“…This increased blood glucose response was not accompanied by an increased response from pancreatic β cells. These data are representative of one of the early β cell functional defects in type 2 diabetes mellitus (19,20), which could have been occurring in progressors, and suggest that insulin secretion in response to an oral glucose challenge is reduced in progressors who are still in the NGT phase.…”

Section: Comparative Analysis Of Initial Demographic and Metabolic Chmentioning

confidence: 72%

Demographic and metabolic characteristics of individuals with progressive glucose tolerance

Mendes

Santos

Padovani

et al. 2009

Braz J Med Biol Res

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We evaluated changes in glucose tolerance of 17 progressors and 62 non-progressors for 9 years to improve our understanding of the pathogenesis of type 2 diabetes mellitus. Changes in anthropometric measurements and responses to an oral glucose tolerance test (OGTT) were analyzed. We identified 14 pairs of individuals, one from each group, who were initially normal glucose tolerant and were matched for gender, age, weight, and girth. We compared initial plasma glucose and insulin curves (from OGTT), insulin secretion (first and second phases) and insulin sensitivity indices (from hyperglycemic clamp assay) for both groups. In the normal glucose tolerant phase, progressors presented: 1) a higher OGTT blood glucose response with hyperglycemia in the second hour and a similar insulin response vs non-progressors; 2) a reduced first-phase insulin secretion (2.0 ± 0.3 vs 2.3 ± 0.3 pmol/L; P < 0.02) with a similar insulin sensitivity index and a lower disposition index (3.9 ± 0.2 vs 4.1 ± 0.2 μmol·kg -1 ·min -1 ; P < 0.05) vs non-progressors. After 9 years, both groups presented similar increases in weight and fasting blood glucose levels and progressors had an increased glycemic response at 120 min (P < 0.05) and reduced early insulin response to OGTT (progressors, 1st: 2.10 ± 0.34 vs 2nd: 1.87 ± 0.25 pmol/mmol; non-progressors, 1st: 2.15 ± 0.28 vs 2nd: 2.03 ± 0.39 pmol/mmol; P < 0.05). Theses data suggest that β-cell dysfunction might be a risk factor for type 2 diabetes mellitus.

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Disproportionate elevation of immunoreactive proinsulin in Type 2 (non-insulin-dependent) diabetes mellitus and in experimental insulin resistance

Cited by 288 publications

References 13 publications

Hyperinsulinaemia in obesity is not accompanied by an increase in serum proinsulin/insulin ratio in groups of human subjects with and without glucose intolerance

Hyperinsulinaemia in obesity is not accompanied by an increase in serum proinsulin/insulin ratio in groups of human subjects with and without glucose intolerance

Multiple metabolic abnormalities in normal glucose tolerant relatives of NIDDM families

Demographic and metabolic characteristics of individuals with progressive glucose tolerance

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