Service, F. John

The quality of the epidemiological data on diabetic neuropathies remains poor for a variety of reasons. They include variability in 1) ascertainment of diabetes, 2 the clinical varieties of diabetic patients studied, 3) characterization of neurological dysfunction, 4) abnormal limits for neurological examinations and tests, 5) minimal criteria for neuropathy, 6) correct attribution of nondiabetic neurological disease, 7) correct attribution of type of neuropathy, 8) estimating neuropathy from use of multiple tests, and 9) estimating severity of polyneuropathy. We have tried to remedy these shortcomings in the Rochester Diabetic Neuropathy Study (RDNS). It was not possible to adequately characterize and quantitate diabetic polyneuropathies using only one or two clinical or test abnormalities. To estimate severity of diabetic polyneuropathy, the results of the neurological examination and abnormalities of nerve conduction, quantitative sensory tests, and quantitative autonomie tests were combined into a composite score. One begins by scoring a standard test of neurological deficits (impairments) of the lower limbs (NIS[LL]) and adds to this transformed numbers for percentile abnormality of seven good functional tests. This NIS(LL)+7 tests score appears to provide a much more comprehensive and stable numeric score by which to diagnose and grade severity of diabetic polyneuropathy than does the use of individual clinical or test results. This test score should be useful as a measure of change in diabetic polyneuropathy for purposes of medical practice, epidemiology studies, and controlled clinical trials. The staging approach that we introduced previously continues to provide an important measure of overall severity of diabetic polyneuropathy, taking into account both symptoms and impairments.

To determine the effects of insulin on dietary and endogenous leucine metabolism, five normal subjects, seven insulin-insufficient insulin-dependent (IDDM) diabetic patients, and five diabetic patients controlled with continuous subcutaneous insulin infusion (CSII) were studied before and for 8 h after ingestion of a chemically defined elemental test meal (10 cal/kg) containing crystalline amino acids. L-[1-14C]leucine was included in the meal to trace the entry and oxidation of the dietary leucine. Total (meal + endogenous) entry of leucine into the circulation was estimated with a constant infusion of [2H3]leucine. Postabsorptive and meal-related increases in the plasma leucine concentration were greater (P < .05) in the insulin-insufficient IDDM than in the normal subjects but returned to near-normal values with CSII. Baseline leucine flux was ∼40% greater in the insulin-insufficient IDDM than in normal subjects (2.17 ± 0.17 vs. 1.55 ± 0.15 μmol · kg−1 · min−1, respectively; .05 < P < .01) but were near normal during CSII treatment (1.85 ± 0.25 μmol · kg−1 · min−1). Furthermore, total leucine entry during meal absorption was greater in the insulin-insufficient IDDM (1.41 ± 0.10 mmol · kg−1.8 h−1) than in either normal (0.96 ± 0.08 mmol · kg−1 · 8 h−1, P < .01) or IDDM subjects during CSII treatment (1.09 ± 0.11 mmol · kg−1 · 8 h−1, P < .05). Fractional oxidation (∼40–50%) and entry of dietary leucine were similar in all three groups. The calculated rate of leucine entry from endogenous proteins over the 8 h of study in insulin-insufficient IDDM (1.04 ± 0.12 mmol · kg−1 · 8 h−1) was significantly greater than in normal subjects (0.64 ± 0.07 mmol · kg−1 · 8 h−, P < .01) or in IDDM subjects during CSII treatment (0.76 ± 0.10 mmol · kg−1 · 8 h−1, P < .05). However, during meal absorption, the calculated rate of leucine entry from endogenous protein was significantly suppressed below baseline only in the normal subjects. In summary, during absorption of a mixed meal, 1) one-third of the leucine entering the peripheral plasma space is derived from the diet in normal humans; 2) the rate of absorption and oxidation of dietary leucine in IDDM is normal regardless of adequacy of insulin therapy; and 3) postprandial hyperleucinemia in poorly controlled diabetic patients is at least partly the result of inadequate suppression of the entry rate of leucine from endogenous protein, suggesting persistence of excessive rates of proteolysis, which is at least partly corrected by intensified insulin treatment. Thus, insulin-mediated suppression of endogenous proteolysis is an integral part of protein anabolism during meal absorption.

The proposed contribution of glucose variability to the development of the complications of diabetes beyond that of glycemic exposure is supported by reports that oxidative stress, the putative mediator of such complications, is greater for intermittent as opposed to sustained hyperglycemia. Variability of glycemia in ambulatory conditions defined as the deviation from steady state is a phenomenon of normal physiology. Comprehensive recording of glycemia is required for the generation of any measurement of glucose variability. To avoid distortion of variability to that of glycemic exposure, its calculation should be devoid of a time component.

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.

To assess the feasibility of preprogramming an open-loop device with insulin flow rates generated by the Biostator Glucose Controller, comparisons were made in 10 juvenile-onset diabetic patients between meals of equal size and composition taken in the morning, at noon, and in the evening and a bedtime snack during a 24-h period of Biostator glucose control. Four additional diabetic patients had Biostator glucose control for 72 h. Similar amounts of insulin were infused for the meals taken at differing times of the day and, except for the morning meal, for the same meal on two successive days. The meal-related glycemic patterns expressed as mean indices of meal excursions (MIME) were similar for meals of identical size and composition during a single day and for the same meal taken on two consecutive days. Preliminary results using an open-loop device preprogrammed by the Biostator system, although encouraging, underscore the deficiency of the subcutaneous route viz. the delayed entry of insulin into the circulation in achieving normal glucose levels and patterns.