Multiple metabolic abnormalities in normal glucose tolerant relatives of NIDDM families

Abstract

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

Offspring of Patients With Diabetes Exhibit a Clustering of Psychosocial Distress and Inflammatory and Metabolic Risk Factors

“…A positive parental history was not associated with sex, ethnicity, fasting glucose, age, C-reactive protein, interleukin-6, anger, depression, or social support. Similar to previous observations, subjects with a family history of diabetes had a higher BMI (4,5) (27 ± 6.6 vs. 24.5 ± 3.8 kg/m 2 , P = 0.07), significantly higher insulin resistance as derived from homeostatis model assessment (5) (median 1.70 [interquartile range 1.19–1.90] vs. 1.30 [0.80–1.82], P = 0.04), and significantly higher fasting plasma insulin (5) (10.3 ± 9 vs. 6.7 ± 4 μU/ml, P = 0.02). However, the relationships of insulin resistance and fasting plasma insulin to parental history were mediated by BMI but not age, ethnicity, or sex.…”

Diabetes and Cardiovascular Disease

“…1,2 Insulin secretion declines with advancing age, 3,4 and this decline may be accelerated by genetic factors. 5,6 Insulin resistance typically precedes the onset of type 2 diabetes and is commonly accompanied by other cardiovascular risk factors: dyslipidemia, hypertension, and prothrombotic factors. 7,8 The common clustering of these risk factors in a single individual has been called the metabolic syndrome.…”

Impaired beta cell glucose sensitivity and whole-body insulin sensitivity as predictors of hyperglycaemia in non-diabetic subjects

“…Insulin insensitivity, frequently linked to increased total and central adiposity, is a key predisposing factor [2,3]. However, impaired pancreatic beta cell function is an essential element in the development of abnormal glucose tolerance.…”