Citations

Type 2 diabetes is characterized by impaired insulin secretion. Some but not all studies suggest that a decrease in β-cell mass contributes to this. We examined pancreatic tissue from 124 autopsies: 91 obese cases (BMI >27 kg/m2; 41 with type 2 diabetes, 15 with impaired fasting glucose [IFG], and 35 nondiabetic subjects) and 33 lean cases (BMI <25 kg/m2; 16 type 2 diabetic and 17 nondiabetic subjects). We measured relative β-cell volume, frequency of β-cell apoptosis and replication, and new islet formation from exocrine ducts (neogenesis). Relative β-cell volume was increased in obese versus lean nondiabetic cases (P = 0.05) through the mechanism of increased neogenesis (P < 0.05). Obese humans with IFG and type 2 diabetes had a 40% (P < 0.05) and 63% (P < 0.01) deficit and lean cases of type 2 diabetes had a 41% deficit (P < 0.05) in relative β-cell volume compared with nondiabetic obese and lean cases, respectively. The frequency of β-cell replication was very low in all cases and no different among groups. Neogenesis, while increased with obesity, was comparable in obese type 2 diabetic, IFG, or nondiabetic subjects and in lean type 2 diabetic or nondiabetic subjects. However, the frequency of β-cell apoptosis was increased 10-fold in lean and 3-fold in obese cases of type 2 diabetes compared with their respective nondiabetic control group (P < 0.05). We conclude that β-cell mass is decreased in type 2 diabetes and that the mechanism underlying this is increased β-cell apoptosis. Since the major defect leading to a decrease in β-cell mass in type 2 diabetes is increased apoptosis, while new islet formation and β-cell replication are normal, therapeutic approaches designed to arrest apoptosis could be a significant new development in the management of type 2 diabetes, because this approach might actually reverse the disease to a degree rather than just palliate glycemia.

Cystic fibrosis (CF) patients are reported to experience chronic protein catabolism. Since diabetes or impaired glucose tolerance (IGT) is common in CF, we hypothesized that their protein catabolic state is related to reduced insulin secretion or reduced insulin action. A total of 12 clinically stable adult CF patients with abnormal glucose tolerance and 12 age-, sex-, and lean body mass–matched healthy control subjects underwent protein turnover studies using l-[1-13C]leucine, l-[15N]phenylalanine, and l-[2H4]tyrosine, with and without exogenous insulin infusion. In the baseline fasting state, protein metabolism was entirely normal in CF patients, with no evidence of increased protein catabolism. In contrast, striking abnormalities were seen in CF patients when insulin was infused, since they did not experience normal suppression of the appearance rates of leucine, phenylalanine, or tyrosine (indexes of protein breakdown). At an insulin concentration of 45 ± 2 μU/ml, normal control subjects suppressed the leucine appearance rate by 19 ± 5% (P < 0.01), ketoisocaproate appearance rate by 10 ± 3% (P = 0.03), tyrosine appearance rate by 11 ± 2% (P = 0.03), and phenylalanine appearance rate by 6 ± 3% (P = 0.07). Phenylalanine conversion to tyrosine decreased by 22 ± 7% (P = 0.03). At a similar insulin concentration of 44 ± 3 μU/ml, normal suppression of amino acid appearance did not occur in CF. The leucine appearance rate decreased by 4 ± 2% (P = 0.65), ketoisocaproate appearance rate by 1 ± 2% (P = 0.94), tyrosine appearance rate by 0 ± 6% (P = 0.56), phenylalanine appearance rate by 5 ± 6% (P = 0.34), and phenylalanine conversion to tyrosine by 5 ± 6% (P = 0.95). Poor suppression of the amino acid appearance rate in CF was not related to previously documented glucose tolerance status (IGT or CF-related diabetes without fasting hyperglycemia), fasting insulin levels, the acute insulin response, insulin sensitivity, cytokine or counterregulatory hormone levels, resting energy expenditure, caloric intake, pulmonary function, or clinical status. Protein synthesis was not significantly affected by insulin infusion in either normal control subjects or CF patients. In conclusion, clinically stable adult CF patients have normal indexes of protein breakdown and synthesis in the fasting state. In contrast, elevation of plasma insulin to physiological postprandial levels fails to normally suppress indexes of protein breakdown. It is therefore likely that inability to spare protein during the postprandial state is the cause of protein catabolism in these patients.

To examine if postprandial splanchnic/hepatic free fatty acid (FFA) delivery is increased in upper-body (UB) obesity, and to determine the adipose tissue depots responsible for the greater postprandial FFA availability, we measured systemic and regional uptake and release of FFAs ([1-(14)C]palmitate) before and during a 5-h frequent-feeding mixed meal in eight UB and eight lower-body (LB) obese women. Postabsorptive FFA flux and splanchnic FFA delivery were not different in UB and LB obese women; however, postprandial FFA concentrations (257 +/- 45 vs. 81 +/- 12 micromol/l, P < 0.0001), FFA flux (8.5 +/- 1.2 vs. 3.9 +/- 0.8 micromol x kg(-1) fat-free mass x min(-1), P < 0.0001), splanchnic FFA delivery (275 +/- 45 vs. 88 +/- 24 micromol/min, respectively, P < 0.005), and estimated hepatic FFA delivery were greater in UB than LB obese women. Nonsplanchnic UB adipose tissue FFA release was greater in UB than in LB obese women (276 +/- 71 vs. 97 +/- 37 micromol/min, respectively, P < 0.05) and accounted for the greater postprandial FFA availability in UB obesity. Postprandial leg glucose uptake was less in UB than in LB obese women (8.4 +/- 5.1 vs. 22.9 +/- 2.6 micromol x kg(-1) leg fat-free mass x min(-1), P < 0.05). We conclude that the elevated postprandial FFA release observed in UB obese women originates from the nonsplanchnic UB fat, not visceral fat. These results suggest that visceral fat may be a marker for, but not the source of, excess postprandial FFAs in obesity.

Retinopathy is an important sequela of diabetes mellitus, but clinical risk factors for this condition have rarely been assessed in a geographically defined population. In this population-based study, the 1135 Rochester, Minnesota, residents with diabetes mellitus initially diagnosed between 1945 and 1969 (incidence cohort) were followed through their complete medical records in the community to January 1, 1982. Because most of the cases of diabetic retinopathy in Rochester residents developed in patients with non-insulin-dependent diabetes mellitus (NIDDM), risk factors for diabetic retinopathy were examined in this group (N = 1031). A proportional hazards model identified the following risk factors for diabetic retinopathy in NIDDM: elevated initial fasting blood glucose level, marked obesity, and earlier age at onset of diabetes. Stratified analyses indicated that duration of diabetes was also significantly associated with an increased risk of retinopathy. Two secular trends, increasing detection of “mild” NIDDM and decreasing risk of diabetic retinopathy, had a major effect on retinopathy risk assessment. These data also suggest that insulin therapy is not an independent risk factor for diabetic retinopathy.

Ultralente has been used as the basal component of intensive insulin therapy programs. To determine the degree to which a single daily subcutaneous injection of beef ultralente provides stable basal insulin concentrations, plasma free insulin concentrations were measured in six insulin-dependent diabetic patients over a 40-h period. All short-acting insulin was withheld during this interval. Each patient had been maintained on a chronic ultralente based program before study. Little if any evidence of a temporal peak in plasma insulin concentrations was observed. Although considerable variation in plasma insulin concentrations was observed in one individual, beef ultralente provided relatively stable plasma insulin concentrations in the group as a whole. Beef ultralente appears to be a reasonable insulin preparation to use as the basal component in an intensive insulin therapy program.

Both basal and postprandial pancreatic polypeptide (PP) concentrations were exaggerated twofold in lean NIDDM patients, whereas they were normal in lean IDDM and obese NIDDM patients who were hyperglycemic as a result of partial insulin withdrawal. Insulin infusion from an artificial endocrine pancreas, which resulted in fasting euglycemia and near-normoglycemia postprandially, had no effect on PP responses in any of the diabetic patients. No postprandial PP responses were observed in totally pancreatectomized (TPX) patients. Excessive basal and postprandial concentrations of PP in diabetes appear to be related to both leanness and residual beta cell function and, therefore, potential markers for lean NIDDM.

Among the 1135 Rochester residents discovered to have diabetes in the period 1945–69, the prevalence of retinopathy was 2.6% at the time of initial diagnosis. Among those free of retinopathy at diagnosis of diabetes, the subsequent incidence of any retinopathy was 17.4 per 1000 person-years and for proliferative retinopathy alone was 1.6 per 1000 person-years, based on 12,000 person-years of follow-up. The incidence rate of retinopathy was almost three times greater among residents with insulin-dependent (IDDM) than with non-insulin-dependent diabetes (NIDDM); however, the actual number of retinopathy cases was over four times greater among the more numerous residents with NIDDM. By 20 yr after diagnosis of diabetes, the cumulative incidence of retinopathy approached 70% among IDDM subjects and was 30% and 36%, respectively, among the obese and nonobese NIDDM residents. The epidemiologic patterns for proliferative retinopathy were qualitatively similar to those for nonproliferative retinopathy. The risk of blindness was greater among those with proliferative than with nonproliferative retinopathy but was substantial even for those without retinopathy. Most blindness was caused by factors other than isolated diabetic retinopathy.

In a population-based investigation among the residents of Rochester, Minnesota, the diabetes mortality rate was 8.5 per 100,000 person-years with diabetes as the underlying cause of death, 31.5 per 100,000 person-years with diabetes as an underlying or contributory cause, and 82.7 per 100,000 person-years if all deaths among diabetic individuals were counted. Diabetes was not mentioned on the certificate in 62% of the 428 diabetic deaths during 1965–1974. When the clinical characteristics of the subgroup of mortality cases in 1969 were compared with those of the prevalence cases on 1 January 1970, it was found that mortality cases tended to be older, were more often on insulin therapy, and were more likely to have macro- and microvascular complications. Because mortality data are sometimes used to infer trends and characteristics for the diabetic population at large, it is important to recognize these biases.

We reviewed the records of pregnant diabetic women attended at Mayo Clinic during the years 1950–79 and matched each nonaborted diabetic pregnancy with two control pregnancies. Abortions occurred in 49 of 277 diabetic pregnancies (17.7%). The relative risk of other adverse outcomes of pregnancy (± 95% confidence interval) in comparison with controls was as follows: perinatal mortality, 7.0 (3.6–13.8); major congenital birth defects, 6.3 (2.8–14.2); and respiratory distress, 9.0 (4.5–17.9). Diabetic ketoacidosis resulted in fetal death in 5 of 18 cases. Patients with mean fasting blood glucose levels of ≤ 140 mg/dl had a perinatal mortality of 81 per 1000 births and an incidence of respiratory distress and congenital birth defects of 18.9% and 9.9%, respectively. Patients with mean blood glucose levels > 140 mg/dl had corresponding rates of 306 per 1000, 20.4%, and 11.2%, respectively. Hydramnios occurred almost exclusively in diabetic women, and its presence was associated with a twofold increase in the frequency of perinatal death. Analysis of diabetic pregnancy outcome by decade showed no appreciable decrease in the occurrence of perinatal mortality, congenital birth defects, or respiratory distress over the 30-yr period.

Of all the known diabetic individuals residing in the community of Rochester, Minnesota, only about one-half would have been recognized through a review of the medical records of 1 yr. Only one-fifth of the diabetic residents were hospitalized during the index year and a similarly small proportion were attended in a diabetes clinic. This selective process produced distortion in the apparent clinical spectrum of diabetes observed at different levels in the medical care system. Notable was overestimation of the relative importance of insulin-dependent diabetes and of the vascular complications of diabetes among hospital and diabetes clinic patients. Referral bias should be taken into account when differences are noted in the epidemiologic features of diabetes as reported from different types of medical care settings.