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When stable and near-normoglycemic, patients with "A-β+" ketosis-prone diabetes (KPD) manifest accelerated leucine catabolism and blunted ketone oxidation, which may underlie their proclivity to develop diabetic ketoacidosis (DKA). To understand metabolic derangements in A-β+ KPD patients during DKA, we compared serum metabolomics profiles of adults during acute hyperglycemic crises, without ( n = 21) or with ( n = 74) DKA, and healthy control subjects (n = 17). Based on 65 kDa GAD islet autoantibody status, C-peptide, and clinical features, 53 DKA patients were categorized as having KPD and 21 type 1 diabetes (T1D); 21 nonketotic patients were categorized as having type 2 diabetes (T2D). Patients with KPD and patients with T1D had higher counterregulatory hormones and lower insulin-to-glucagon ratio than patients with T2D and control subjects. Compared with patients withT2D and control subjects, patients with KPD and patients with T1D had lower free carnitine and higher long-chain acylcarnitines and acetylcarnitine (C2) but lower palmitoylcarnitine (C16)-to-C2 ratio; a positive relationship between C16 and C2 but negative relationship between carnitine and β-hydroxybutyrate (BOHB); higher branched-chain amino acids (BCAAs) and their ketoacids but lower ketoisocaproate (KIC)-to-Leu, ketomethylvalerate (KMV)-to-Ile, ketoisovalerate (KIV)-to-Val, isovalerylcarnitine-to-KIC+KMV, propionylcarnitine-to-KIV+KMV, KIC+KMV-to-C2, and KIC-to-BOHB ratios; and lower glutamate and 3-methylhistidine. These data suggest that during DKA, patients with KPD resemble patients with T1D in having impaired BCAA catabolism and accelerated fatty acid flux to ketones-a reversal of their distinctive BCAA metabolic defect when stable. The natural history of A-β+ KPD is marked by chronic but varying dysregulation of BCAA metabolism., (© 2021 by the American Diabetes Association.)

Acute and chronic hyperglycemia are proinflammatory states, but the status of proinflammatory cytokines and markers of oxidative stress and cardiovascular risks is not known in hyperglycemic crises of diabetic ketoacidosis (DKA) and nonketotic hyperglycemia (NKH). We studied 20 lean and 28 obese patients with DKA, 10 patients with NKH, and 12 lean and 12 obese nondiabetic control subjects. We measured 1) proinflammatory cytokines (tumor necrosis factor-alpha, interleukin [IL]-6, IL1-beta, and IL-8), 2) markers of cardiovascular risk (C-reactive protein [CRP], homocysteine, and plasminogen activator inhibitor-1 [PAI-1]), 3) products of reactive oxygen species (ROS; thiobarbituric acid [TBA]-reacting material, and dichlorofluorescein [DCF]), and 4) cortisol, growth hormone (GH), and free fatty acids (FFAs) on admission (before insulin therapy) and after insulin therapy and resolution of hyperglycemia and/or ketoacidosis. Results were compared with lean and obese control subjects. Circulating levels of cytokines, TBA, DCF, PAI-1, FFAs, cortisol, and GH on admission were significantly increased two- to fourfold in patients with hyperglycemic crises compared with control subjects, and they returned to normal levels after insulin treatment and resolution of hyperglycemic crises. Changes in CRP and homocysteine in response to insulin therapy did not reach control levels after resolution of hyperglycemia. We conclude that DKA and NKH are associated with elevation of proinflammatory cytokines, ROS, and cardiovascular risk factors in the absence of obvious infection or cardiovascular pathology. Return of these values to normal levels with insulin therapy demonstrates a robust anti-inflammatory effect of insulin.

It has been suggested that the hemodynamic derangements present in diabetic ketoacidosis are the results not only of profound volume depletion but also of the effects of increased production of vasodilating prostaglandins (PGs), principally PGI2, released by adipose tissue. In animal and in vitro models, prostaglandin synthesis is increased during insulin deficiency. We assessed the effects of short-term ketosis on the metabolic and hemodynamic variables of 10 IDDM patients free from long-term complications and of 9 normal control subjects after a 7-day randomized double-blind indomethacin (INDO) (50 mg q.i.d.) or placebo treatment period. Calf blood flow (CBF), postocclusive reactive hyperemia (PORH), and recovery half-time (an index of overall perfusion) after PORH were measured by plethysmography. Left ventricular and myocardial functions were also studied in each different condition during placebo and INDO treatment in IDDM patients. During placebo treatment, the increase in CBF during ketosis was higher (1.75 +/- 0.29 ml / min / 100 ml muscle) than during INDO (0.85 +/- 0.17 ml / min) / 100 ml muscle; P = 0.007). PORH was similar in baseline conditions, during ketosis, and in recovery in both the placebo and INDO arms. Recovery half-time significantly increased during placebo (10 +/- 2; 200%; P < 0.01) but not during INDO (1 +/- 1; 106%; NS) treatment. In normal control subjects, insulin deficiency did not induce any significant effect on hemodynamic variables. In IDDM patients, during placebo treatment, ketosis increased both the cardiac index (from 3.4 +/- 0.7 to 4.1 +/- 0.81 / min / m; P < 0.01) and the stroke index (from 42 +/- 8 to 49 +/- 7 ml/m2; P < 0.01) without changes in left ventricular ejection fraction but with a significant increase in both left and right ventricular end-diastolic volumes. Metabolic recovery induced a normalization of these parameters. INDO treatment significantly blunted these alterations. In summary, we showed that during acute insulin deficiency, INDO-sensitive mechanisms mediate vascular disturbances. Moreover, INDO treatment was capable of completely preventing the cardiac venous return and the left ventricular alterations. INDO does not interfere with the overall ketogenetic process or with insulin-induced metabolic recovery.

Our preliminary data indicate that 15% of African-American patients presenting with diabetic ketoacidosis (DKA) are obese. To determine underlying mechanisms, we analyzed the clinical characteristics and indexes of insulin secretion and insulin sensitivity in 35 obese patients with DKA, 22 obese patients with hyperglycemia, 10 lean patients with DKA, and 10 obese nondiabetic subjects. Studies were performed 1 day after resolution of DKA and after 12 weeks of follow-up. At presentation, both obese DKA and obese hyperglycemic patients had no detectable insulin response to intravenous glucose, but they did respond to glucagon administration. The acute insulin response (AIR) to glucagon in obese DKA patients (0.9 +/- 0.1 ng/ml, P < 0.01), but significantly greater than in lean patients with DKA (0.1 +/- 0.1 ng/ml, P < 0.01). After 12 weeks of follow-up, the AIR to glucose improved in both groups of obese diabetic patients but remained significantly lower than in nondiabetic control subjects (both P < 0.01). In contrast, the AIR to glucagon was not significantly different from that in obese control subjects. Insulin sensitivity was decreased in both groups of obese diabetic patients at presentation and improved after follow-up to levels similar to those in obese nondiabetic control subjects. Reactivity with islet cell antibodies was not detected in any of the patients. During follow-up, 25 of 35 obese DKA and 16 of 22 hyperglycemic patients were able to discontinue insulin therapy, with continued good metabolic control. Our results indicate that in African-Americans, obese patients with DKA represent a subset of type II diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

The objective of this study is to understand the metabolic and immunologic basis of diabetes in adult blacks with diabetic ketoacidosis (DKA). Twenty-one black adults presenting with DKA ([mean +/- SD] blood pH = 7.18 +/- 0.09, plasma glucose = 693 +/- 208 mg/dl, and positive serum ketones) had a subsequent clinical course of non-insulin-dependent diabetes mellitus (NIDDM). Human leukocyte antigens (HLAs) DR and DQ and antibodies to glutamic acid decarboxylase (GAD) and islet cell cytoplasmic proteins (ICP) were measured to assess autoimmunity. Insulin action was evaluated by the euglycemic insulin clamp, and insulin secretion was measured by C-peptide responses to oral glucose. Ketoacidosis was treated with insulin. Two subjects had a precipitating illness; four had a history of NIDDM. At the time of study, subjects' glycemic control was good (HbA1c = 5.7 +/- 1.6%). Nine subjects were treated with insulin, and 12 were on either sulfonylurea treatment or diet alone. Men (n = 12) were younger than women (n = 9) (40.8 +/- 9.8 and 51.1 +/- 6.3 years of age, respectively, P < 0.05) but similar in body mass index (27.8 +/- 2.7 and 29.98 +/- 4.1 kg/m2, respectively). Antibodies to GAD and ICP were absent. All but one subject was insulin resistant compared with normal subjects (glucose disposal 3.56 +/- 0.04 vs. 6.86 +/- 0.02 mg.kg-1.min-1), and insulin secretion was lower. HLA DR3 and DR4 frequency was higher than in nondiabetic black control subjects (65 vs. 30%, P < 0.012).(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma glucagon levels were measured in young individuals with severe, insulin-dependent, juvenile-onset diabetes mellitus to study whether differences in glucagon secretion were related to ketosis proneness and resistance. Fasting glucagon levels were similarly elevated in both classical, ketosis-prone, type I diabetic subjects and ketosis-resistant, type "J" subjects [70 +/- 7 pmol/L (mean +/- SEM) and 81 +/- 10 pmol/L, respectively] compared with nonobese, nondiabetic controls (36 +/- 3 pmol/L, P less than 0.01). After oral glucose administration, however, glucagon responses were strikingly dissimilar in the two groups. In type I diabetic individuals, glucagon rose paradoxically during OGTT, by 21 +/- 4 pmol/L, an increase of 33 +/- 10%; on the other hand, glucagon levels in type "J" diabetic individuals fell by 28 +/- 7 pmol/L, a decrease of 33 +/- 5%. There was no measurable increase in plasma free insulin during OGTT in either group. Postprandial glucagon suppressibility may be relevant to the ketosis resistance that is characteristic of type "J" diabetes.

Although somatomedin levels may be low in animals with experimental diabetes, values in humans have generally been normal. Because humans with severely decompensated diabetes have not been studied, we characterized somatomedin C responses during metabolic restoration in 21 patients with diabetic ketoacidosis. Somatomedin C values were compared with those of 25 outpatient controls. Somatomedin C in controls (mean +/- SE) was 0.72 +/- 0.09 U/ml, 69% of the mean sex-adjusted normal level; 28% of patients had values below the lower limit of normal. In ketoacidotic subjects, initial somatomedin C was 0.43 +/- .06 U/ml, 33% of the mean normal level; 52% of subjects had somatomedin C below the lower limit of normal. Initial levels in ketoacidotic subjects were unrelated to presenting levels of glucose, bicarbonate, ketones, or blood urea nitrogen but were significantly lower in patients of less than ideal body weight (0.30 vs. 0.58 U/ml, P less than .03). Presenting levels of somatomedin C in ketoacidotic subjects were significantly lower than in controls (P less than .02). During insulin-infusion therapy, somatomedin C rose to a peak of 1.16 +/- 0.21 U/ml after 28 h, significantly higher than initial levels (P less than .05). With continued subcutaneous insulin, somatomedin C fell to a nadir after an additional 22 h then rose more slowly to a final value of 0.75 +/- 0.12 U/ml, significantly higher than the nadir (P less than .05) but lower than peak values; final values in the ketoacidotic subjects were comparable to outpatient somatomedin C levels.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of "low-dose" (6--10 U/h) insulin treatment on the rate of decline of plasma glucose concentration was determined in 15 diabetic subjects admitted in ketoacidosis (plasma glucose = 948 79 mg/dl) and in six normal volunteers rendered hyperglycemic by a combined infusion of somatostatin and glucose (plasma glucose = 653 28 mg/dl). The fractional glucose turnover and the half-time of the fall in plasma glucose during insulin treatment were both 10-fold reduced (P less than 0.001) in the diabetics as compared with the controls. In the ketoacidotic subjects, the mean glucose clearance during insulin treatment was only 8% of that in the controls (P less than 0.001). In the normal subjects, tissue glucose clearance during insulin treatment of the hyperglycemia (5.8 0.7 ml/min . kg) was similar to that measured in the same subjects using a standard technique to quantitate insulin sensitivity (euglycemic insulin clamp). In the ketoacidotic patients, a history of prior insulin therapy, but not the degree of hyperglycemia at the time of admission, was associated with a more rapid rate of decline of plasma glucose in response to insulin treatment. We conclude that marked insulin resistance is present in virtually all diabetics in ketoacidosis.

Phenformin concentrations were measured in serum from seven patients with phenformin-associated lactic acidosis, and initial values ranging from 20 to 625 ng./ml. were obtained. Five of the seven patients had serum concentrations within the usual therapeutic range of up to 241 ng./ml. Serum phenformin concentrations were measured serially, and apparent half-lives of 5, 25, and 30 hours were obtained in three patients with serum creatinine concentrations of 1.7, 7.6, and 6.0 mg./dl., respectively. Although the half-life of phenformin was prolonged in azotemic patients, no correlation between serum creatinine concentration and serum phenformin could be demonstrated; furthermore, the severity of lactic acidosis as measured by arterial pH and lactate concentration did not correlate with the serum creatinine concentration.

Unusual increases in the minor hemoglobin components (Hb AIa, b, c) known to be elevated in diabetes mellitus were found in states of relative or absolute insulinopenia: diabetic ketoacidosis, steroid-induced diabetes, insulin-dependent diabetes in cystic-fibrosis patients, and cystic fibrosis occurring in infants who have a marked suppression of insulin secretion. In ketoacidotic diabetics, it required at least a month for high Hb AI levels (16.9 +/- 2.6 per cent) to stabilize at nonacidotic levels (12.8 +/- 0.3 per cent), suggesting that decreases occur only as new red cells form under conditions less favorable to Hb AI synthesis. Abnormal amounts os Hb A and Hb AI resisted removal from diabetic red-cell membranes by low ionic buffers but yielded to hypotonic Tris buffer. Their removal resulted in simultaneous elution of peripheral and integral membrane proteins. It is suggested that Hb so firmly bound could reduce membrane elasticity and cell deformability, characteristics so vital to normal red cell movement through the microvasculature.

Concentrations of the antidiuretic hormone, arginine vasopressin, were measured in 28 patients with severe hyperglycemia to determine if abnormalities in hormonal regulation of water excretion could contribute to the extreme dehydration of uncontrolled diabetes mellitus. Vasopressin levels were markedly elevated in both nonketotic and ketotic patients, indicating that vasopressin deficiency plays no role in the polyuria that accompanies hyperglycemia. Instead, the observed increases in vasopressin represent an ineffective effort to conserve water in the face of an overwhelming solute diuresis caused by the glucosuria. The reasons for such marked elevations in plasma vasopressin in these diabetic patients are multifactorial. Both groups of diabetic patients had evidence of hypovolemia, which was sufficient in magnitude to stimulate vasopressin release. Furthermore, nausea provided an independent stimulus to vasopressin secretion in many patients. Osmotic stimulation might have resulted from the large fraction of unidentified plasma solutes, but this factor alone was not sufficient to explain the markedly increased concentrations of vasopressin. Whether such elevations in vasopressin could have metabolic and/or hemodynamic effects in uncrontrolled diabetes remains to be established.

Plasma levels of 13,14-dihydro-15-keto-PGE2, a stable derivative of PGE2, are elevated in rats with diabetic ketoacidosis (DKA) and decrease in response to insulin therapy. In patients with insulin-dependent diabetes mellitus type I (IDDM) the plasma levels of this derivative also rise in response to insulin withdrawal and then fall in response to insulin replacement. We wished to determine whether the level of this substance is elevated acutely when patients present with DKA and to determine whether the levels fall during treatment. We also wished to identify the origin of the circulating 13,14-dihydro-15-keto-PGE2 in patients with DKA and in normal fasting subjects. We measured the plasma level of 13,14-dihydro-15-keto-PGE2 in five patients with DKA and in six normal subjects during a 24-h fast. In the patients with DKA before treatment, the plasma 13,14-dihydro-15-keto-PGE2 level was threefold above normal. During therapy, the 13,14-dihydro-15-keto-PGE2 level fell toward normal. There was a significant direct correlation between the plasma free fatty acid (FFA) level and the plasma 13,14-dihydro-15-keto-PGE2 level before and during treatment. In addition, the inverse correlation between the plasma free-insulin level and the plasma 13,14-dihydro-15-keto-PGE2 level approached significance (P = .06). In contrast, in the normal fasting subjects the plasma FFA level rose to values comparable to those observed in the patients with DKA, but there was no significant increase in the plasma 13,14-dihydro-15-keto-PGE2 level.(ABSTRACT TRUNCATED AT 250 WORDS)

The defect in host defense that makes the diabetic ketoacidotic (DKA) patient susceptible to mucormycosis has not been identified. Sera from 10 DKA patients and three normal volunteers were tested for their capacity to support the in vitro growth of a common etiologic agent of mucormycosis, Rhizopus oryzae. After equilibration with room air none of the normal or DKA sera, each of which was now extremely alkaline, supported growth of R. oryzae. When the sera were placed in a CO2 atmosphere that permitted simulation of the in vivo clinical pH (normal 7.40 and DKA 7.3-6.6), four of seven DKA sera supported profuse fungal growth. No growth occurred in normal serum. The three DKA sera that did not support fungal growth at pH less than or equal to 7.3 contained less iron (x = 13 micrograms/dl) than the four sera that supported profuse fungal growth (x = 69 micrograms/dl). Increasing the iron content of iron-poor DKA serum that did not support R. oryzae growth allowed profuse growth at acidotic conditions but not at pH greater than or equal to 7.4. Simulated acidotic conditions (pH 7.3-6.6) also decreased the iron-binding capacity of normal serum stepwise from 266 micrograms/dl to 0. Our data indicate that acidosis temporarily disrupts the capacity of transferrin to bind iron and suggest that this alteration abolishes an important host defense mechanism that permits growth of R. oryzae.

The relation between serum and red blood cell (RBC) inorganic phosphate levels, RBC 2,3-diphosphoglycerate (2,3-DPG) levels, RBC nucleotide phosphate (Pn), and RBC total phosphate (Pt) levels were studied during the early phases of treatment and recovery from diabetic ketoacidosis (DKA). A steady drop in serum inorganic phosphate was found during the first 24 hours of insulin treatment and was most profound at 24 hours. No statistically significant changes (P less than 0.05) were found in red cell inorganic phosphate or nucleotide phosphate levels during the 24-hour study period. The levels of total red cell phosphate were lower in this group of patients than in nonacidotic diabetic subjects and decreased slightly after 24 hours of treatment. The red cell 2,3-DPG levels were low at the initiation of therapy and remained low during the 24-hour study period. Glucose, bicarbonate, lactate, and ketone levels fell in linear patterns with treatment. In view of the current evidence for the effects of low 2,3-DPG on oxygen delivery and the relation of low serum phosphate levels to RBC glycolysis and 2,3-DPG formation, this study reemphasizes the need for phosphate replacement during the early phases of treatment of DKA.

Insulin therapy was withdrawn from 15 well-controlled type I diabetic subjects for no longer than 18 h to examine the sequence with which 13,14-dihydro-15-keto-PGE2 (PGE-m), glucagon, norepinephrine, and epinephrine increased in circulating blood in diabetic subjects becoming ketoacidotic. Fourteen of 15 patients had increments in PGE-m; 12/12, 12/15, and 13/15 had increments in glucagon, norepinephrine, and epinephrine, respectively. Six of the 15 patients developed mild diabetic ketoacidosis (DKA) by 12-18 h; all had nonmeasurable C-peptide levels. This DKA group had significantly greater increments of PGE-m (835 +/- 130 versus 276 +/- 111 pg/ml, mean +/- SEM, P less than 0.01) but not glucagon, norepinephrine, or epinephrine compared with the 9 non-DKA patients. In the DKA group, there were significant PGE-m and glucagon increments in the circulation by 3 h, significant norepinephrine increments by 9 h, and epinephrine increments in 5/6 patients by 12 h (not statistically significant) of insulin withdrawal. These studies document that (1) PGE-m accumulates in the circulation during DKA, (2) PGE-m and glucagon increase before catecholamines, and (3) PGE-m, glucagon, and catecholamine levels promptly return to normal levels when insulin therapy is reinstituted. It is suggested that elevated PGE-m levels early in the onset of DKA may represent a host-defense mechanism.

The concentrations of glycolytic intermediates and adenine nucleotides were determined in erythrocytes from patients with diabetic ketoacidosis before and during insulin treatment. Ketoacidosis resulted in an increase in the levels of intermediates above the phosphofructokinase (PFK) step and a marked decrease in the levels of those below this step. Thus, a "crossover" point was seen at the PFK step in a crossover plot. This indicated that the rate of glycolytic flow during ketoacidosis was controlled by PFK and that the reduced level of 2,3-bisphosphoglycerate (2, 3-BPG) was attributed to the inhibition of this enzyme. In vitro studies revealed that acidemia is mainly responsible for the inhibition of PFK, whereas elevated levels of ketone bodies and free fatty acids have no direct bearing on it. Insulin administration produced hypophosphatemia within 8-12 h and it persisted for 24 h or longer. The levels of fructose-6-phosphate and glucose-6-phosphate were decreased transiently during this hypophosphatemic phase, while those of fructose bisphosphate and triose phosphates were increased. This indicated that PFK was activated. Thus, it is no longer reasonable to think that the inhibition of PFK is a factor responsible for a delay in normalization of the 2, 3-BPG level during the recovery phase. The levels of these glycolytic intermediates, including 2, 3-BPG, were normalized within 4 days by appropriate therapy.

Stupor in patients with nonketotic hyperglycemia has been ascribed to hyperosmolarity, but the cause of depressed consciousness in patients with ketoacidosis has been puzzling. In this study, blood pH, serum glucose and sodium concentrations, and serum osmolality were measured in eighty-five consecutive episodes of diabetic ketoacidosis and forty-seven of nonketotic hyperglycemia. In the acidotic patients, as in those with nonketotic hyperglycemia, stupor closely paralleled hyperosmolarity and not the severity of acidemia. Indeed, the mean elevations of serum osmolarity were almost the same in the ketotic and in the nonketotic patients who were deeply obtunded. It seems likely that depression of consciousness in patients with severely uncontrolled diabetes mellitus, if not due to a nonmetabolic disorder, such as acute stroke, is attributable to hyperosmolarity, whether or not ketoacidosis is present.