James H. Warram

Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up study

Type 2 diabetes mellitus is characterised by resistance of peripheral tissues to insulin and a relative deficiency of insulin secretion. To find out which is the earliest or primary determinant of disease, we used a minimum model of glucose disposal and insulin secretion based on intravenous glucose tolerance tests to estimate insulin sensitivity (SI), glucose effectiveness (ie, insulin-independent glucose removal rate, SG), and first-phase and second-phase beta-cell responsiveness in normoglycaemic offspring of couples who both had type 2 diabetes. 155 subjects from 86 families were followed-up for 6-25 years. More than 10 years before the development of diabetes, subjects who developed the disease had lower values of both SI (mean 3.2 [SD 2.4] vs 8.1 [6.7] 10(-3) I min-1 pmol-1 insulin; p < 0.0001) and SG (1.6 [0.9] vs 2.3 [1.2] 10(-2) min-1, p < 0.0001) than did those who remained normoglycaemic). For the subjects with both SI and SG below the group median, the cumulative incidence of type 2 diabetes during the 25 years was 76% (95% confidence interval 54-99). By contrast, no subject with both SI and SG above the median developed the disease. Subjects with low SI/high SG or high SI/low SG had intermediate risks. Insulin secretion, especially first phase, tended to be increased rather than decreased in this prediabetic phase and was appropriate for the level of insulin resistance. The development of type 2 diabetes is preceded by and predicted by defects in both insulin-dependent and insulin-independent glucose uptake; the defects are detectable when the patients are normoglycaemic and in most cases more than a decade before diagnosis of disease.

Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents.

OBJECTIVE To determine whether insulin resistance or insulin deficiency is primary in the pathogenesis of type II diabetes. DESIGN Cohort analytic study of persons with normal glucose tolerance but with a high risk for developing type II diabetes (average follow-up time, 13 years). SETTING Outpatients had an intravenous glucose tolerance test and were contacted periodically to ascertain diagnoses of diabetes. PARTICIPANTS One hundred and fifty-five normal offspring, ranging in age from 16 to 60 years, of two parents with type II diabetes and 186 normal control subjects in the same age range who had no family history of diabetes. MEASUREMENTS AND MAIN RESULTS Two phenotypic characteristics distinguished the offspring of diabetic parents from control subjects. They had slower glucose removal rates (Kg) (P less than 0.01) and higher insulin levels (fasting and during the second phase of insulin response to intravenous glucose; P less than 0.0001) than did control subjects, even after adjustment for differences in obesity. Sixteen percent of the offspring developed type II diabetes. Mean Kg at baseline was 1.7%/min among offspring who subsequently developed diabetes, 2.2%/min among offspring who remained nondiabetic, and 2.3%/min among control subjects. Corresponding means for first-phase insulin were 498, 354, and 373 pM, respectively, whereas second-phase insulin means were 329, 117, and 87 pM, respectively. In multivariate analysis, low Kg and high serum insulin levels independently increased the risk for developing diabetes among the offspring of diabetic parents. CONCLUSIONS One to two decades before type II diabetes is diagnosed, reduced glucose clearance is already present. This reduced clearance is accompanied by compensatory hyperinsulinemia, not hypoinsulinemia, suggesting that the primary defect is in peripheral tissue response to insulin and glucose, not in the pancreatic beta cell.

The changing natural history of nephropathy in type I Diabetes

Events in the natural history of diabetic nephropathy (including the onset of persistent proteinuria and end-stage renal failure) were studied in a cohort of 292 patients with juvenile-onset type I diabetes who were followed for 20 to 40 years. The risk of persistent proteinuria increased rapidly between the fifth and 15th years of diabetes and declined thereafter. This pattern suggests that susceptibility to this complication was limited to a subset of patients and was exhausted over time. Patients with the most frequent severe hyperglycemia (the highest quartile) during the first 15 years of diabetes had a risk of persistent proteinuria that was four and a half times higher than that for those with the least frequent hyperglycemia (the lowest quartile). Patients whose diabetes was diagnosed in the 1930s had twice the risk of persistent proteinuria as those in whom the condition was diagnosed in later decades. Once persistent proteinuria appeared, progression to renal failure almost always followed. Half reached this stage within 10 years, and the interval for progression did not vary according to sex, frequency of hyperglycemia, or calendar year of diagnosis of diabetes. This period, however, was significantly shorter (eight versus 14 years) for patients whose diabetes was diagnosed after puberty than for those who were younger at onset. In conclusion, the development of diabetic nephropathy consists of at least two stages. The onset of proteinuria, although related to the level of exposure to hyperglycemia, appears to be influenced by genetic and/or environmental factors. The second stage, progression to renal failure, seems to be influenced by processes related to maturation or aging.

Predisposition to Hypertension and Susceptibility to Renal Disease in Insulin-Dependent Diabetes Mellitus

Only one third of patients with juvenile-onset insulin-dependent diabetes seem to be susceptible to diabetic nephropathy. To test whether this susceptibility is related to a predisposition to hypertension, we investigated the association of nephropathy with markers of risk for hypertension. We randomly selected 89 patients with insulin-dependent diabetes from a roster of children and adolescents who were seen between 1968 and 1972 at about the time the diagnosis was made. These 89 patients were recalled for examination, as young adults, in 1986 and 1987. Patients with nephropathy (cases, n = 33) were compared with controls without nephropathy (n = 56). Having a parent with hypertension tripled the risk of nephropathy (odds ratio, 3.7; 95 percent confidence interval, 1.4 to 10.1). Moreover, cases had significantly higher values for maximal velocity of lithium-sodium countertransport in red cells than controls (mean maximal velocity +/- SE, 0.51 +/- 0.04 vs. 0.38 +/- 0.02 mmol per liter of cells per hour; P less than 0.05). The excess risk associated with both these indicators of a predisposition to hypertension was evident principally in patients with poor glycemic control during their first decade of diabetes; the odds ratios were 4.5 (95 percent confidence interval, 1.1 to 18.7) for patients with a parental history of hypertension and 7.7 (95 percent confidence interval, 1.8 to 33.8) for patients with a maximal velocity of lithium-sodium countertransport greater than or equal to 0.35 mmol per liter of cells per hour. We conclude that the risk of renal disease in patients with juvenile-onset insulin-dependent diabetes is associated with a genetic predisposition to hypertension. Predisposition to hypertension appears to increase susceptibility for renal disease principally in patients with poor glycemic control.

Magnitude and determinants of coronary artery disease in juvenile-onset, insulin-dependent diabetes mellitus

The risk of premature coronary artery disease (CAD) and its determinants were investigated in a cohort of 292 patients with juvenile-onset, insulin-dependent diabetes mellitus (IDDM) who were followed for 20 to 40 years. Although patients with juvenile-onset IDDM had an extremely high risk of premature CAD, the earliest deaths due to CAD did not occur until late in the third decade of life. After age 30 years, the mortality rate due to CAD increased rapidly, equally in men and women, and particularly among persons with renal complications. By age 55 years the cumulative mortality rate due to CAD was 35 +/- 5%. This was far higher than the corresponding rate for nondiabetic persons in the Framingham Heart Study, 8% for men and 4% for women. Angina and acute nonfatal myocardial infarction followed a similar pattern, as did asymptomatic CAD detected by stress test, so that their combined prevalence rate was 33% among survivors aged 45 to 59 years. Age at onset of IDDM and the presence of eye complications did not contribute to risk of premature CAD. This pattern suggests that juvenile-onset diabetes and its renal complications are modifiers of the natural history of atherosclerosis in that although they profoundly accelerate progression of early atherosclerotic lesions to very severe CAD, they may not contribute to initiation of atherosclerosis.

Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus

The helix-loop-helix (HLH) protein NEUROD1 (also known as BETA2) functions as a regulatory switch for endocrine pancreatic development. In mice homozygous for a targeted disruption of Neurod, pancreatic islet morphogenesis is abnormal and overt diabetes develops due in part to inadequate expression of the insulin gene (Ins2). NEUROD1, following its heterodimerization with the ubiquitous HLH protein E47, regulates insulin gene (INS) expression by binding to a critical E-box motif on the INS promoter. Here we describe two mutations in NEUROD1, which are associated with the development of type 2 diabetes in the heterozygous state. The first, a missense mutation at Arg 111 in the DNA-binding domain, abolishes E-box binding activity of NEUROD1. The second mutation gives rise to a truncated polypeptide lacking the carboxy-terminal trans-activation domain, a region that associates with the co-activators CBP and p300 (refs 3,4). The clinical profile of patients with the truncated NEUROD1 polypeptide is more severe than that of patients with the Arg 111 mutation. Our findings suggest that deficient binding of NEUROD1 or binding of a transcriptionally inactive NEUROD1 polypeptide to target promoters in pancreatic islets leads to the development of type 2 diabetes in humans.

Glycosylated Hemoglobin and the Risk of Microalbuminuria in Patients with Insulin-Dependent Diabetes Mellitus

BACKGROUND The risk of microalbuminuria in patients with insulin-dependent diabetes mellitus (IDDM) is thought to depend on the degree of hyperglycemia, but the relation between the degree of hyperglycemia and urinary albumin excretion has not been defined. METHODS We measured urinary albumin excretion in three random urine samples obtained at least one month apart from 1613 patients with IDDM. Microalbuminuria or overt albuminuria was considered to be present if the ratio of albumin (in micrograms) to creatinine (in milligrams) was 17 to 299 or > or = 300, respectively, for men and 25 to 299 or > or = 300, respectively, for women. Measurements of glycosylated hemoglobin (hemoglobin A1) obtained up to four years before the urine testing were used as an index of hyperglycemia. Twelve percent of the patients had overt albuminuria and were excluded from subsequent analyses. RESULTS The prevalence of microalbuminuria was 18 percent in patients with IDDM. It increased with increasing postpubertal duration of diabetes and, within each six-year interval of disease duration, it increased nonlinearly with the hemoglobin A1 value. For hemoglobin A1 values below 10.1 percent, the slope of the relation was almost flat, whereas for values above 10.1 percent, the prevalence of microalbuminuria rose steeply (P < 0.001). For example, as the hemoglobin A1 value increased from 8.1 to 10.1 percent, the odds of microalbuminuria increased by a factor of 1.3, but as the value increased from 10.1 to 12.1 percent, the odds were increased by a factor of 2.4. CONCLUSIONS The risk of microalbuminuria in patients with IDDM increases abruptly above a hemoglobin A1 value of 10.1 percent (equivalent to a hemoglobin A1c value of 8.1 percent), suggesting that efforts to reduce the frequency of diabetic nephropathy should be focused on reducing hemoglobin A1 values that are above this threshold.

Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci

We carried out a meta-analysis of data from three genome-wide association (GWA) studies of type 1 diabetes (T1D), testing 305,090 SNPs in 3,561 T1D cases and 4,646 controls of European ancestry. We obtained further support for 4q27 (IL2-IL21, P = 1.9 × 10−8) and, after genotyping an additional 6,225 cases, 6,946 controls and 2,828 families, convincing evidence for four previously unknown and distinct risk loci in chromosome regions 6q15 (BACH2, P = 4.7 × 10−12), 10p15 (PRKCQ, P = 3.7 × 10−9), 15q24 (CTSH, P = 3.2 × 10−15) and 22q13 (C1QTNF6, P = 2.0 × 10−8).

Epidemiologic Approach to the Etiology of Type I Diabetes Mellitus and Its Complications

DIABETES arises through two etiologically distinct routes.1 Type I diabetes is the result of immunologically mediated destruction of the pancreatic beta cells, and usually requires replacement ther...

Estrogen Excretion Patterns and Plasma Levels in Vegetarian and Omnivorous Women

We studied 10 vegetarian and 10 nonvegetarian premenopausal women on four occasions approximately four months apart. During each study period, the participants kept three-day dietary records, and estrogens were measured in plasma, urinary, and fecal samples. Vegetarians consumed less total fat than omnivores did (30 per cent of total calories, as compared with 40 per cent) and more dietary fiber (28 g per day, as compared with 12 g). There was a positive correlation between fecal weight and fecal excretion of estrogens in both groups (P less than 0.001), with vegetarians having higher fecal weight and increased fecal excretion of estrogens. Urinary excretion of estriol was lower in vegetarians (P less than 0.05), and their plasma levels of estrone and estradiol were negatively correlated with fecal excretion of estrogen (P = 0.005). Among the vegetarians the beta-glucuronidase activity of fecal bacteria was significantly reduced (P = 0.05). We conclude that vegetarian women have an increased fecal output, which leads to increased fecal excretion of estrogen and a decreased plasma concentration of estrogen.