Exogenous Insulin Antibody Syndrome (EIAS) Presenting in an Elderly, Long-Term Patient with Type 1 Diabetes Mellitus that Resolved with Low-Cost Outpatient Therapy with Mycophenolate Mofetil and Regular Insulin by Pump.

Exogenous insulin antibody syndrome (EIAS) has until recently been a rarely described complication of exogenous insulin therapy. EIAS results not only in hyperglycemia, but also in hypoglycemia and occasionally in ketoacidosis (DKA). The incidence of EIAS is increasing probably due to an overall increase in autoimmunity associated with the coronavirus disease 2019 (Covid-19) epidemic resulting in increasing binding of insulin by antibodies. Herein, we describe a case of EIAS occurring in an elderly patient with longstanding type 1 diabetes mellitus (T1DM) who had progressive loss of glycemic control. It responded positively, as we have previously described, to oral mycophenolate mofetil and the use of soluble regular insulin delivered by continuous subcutaneous insulin infusion (CSII). Therefore, EIAS is an increasingly frequent cause of hyperglycemia with and without DKA, and hypoglycemia in subjects with T1DM. Once diagnosed, they can be treated with mycophenolate mofetil and soluble insulin in an outpatient setting, which will decrease the rate of hospitalization and lower the expense of therapy.

The potential for improved outcomes in the prevention and therapy of diabetic kidney disease through 'stacking' of drugs from different classes.

Aggressive therapy of diabetic kidney disease (DKD) can not only slow the progression of DKD to renal failure but, if utilized at an early enough stage of DKD, can also stabilize and/or reverse the decline in renal function. The currently recognized standard of therapy for DKD is blockade of the renin-angiotensin system with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). However, unless utilized at a very early stage, monotherapy with these drugs in DKD will only prevent or slow the progression of DKD and will neither stabilize nor reverse the progression of DKD to renal decompensation. Recently, the addition of a sodium-glucose cotransporter-2 inhibitor and/or a mineralocorticoid receptor blocker to ACE inhibitors or ARBs has been clearly shown to further decelerate the decline in renal function. The use of glucagon-like peptide-1 (GLP-1) agonists shown promise in decelerating the progression of DKD. Other drugs that may aid in the deceleration the progression of DKD are dipeptidyl peptidase-4 inhibitors, pentoxifylline, statins, and vasodilating beta blockers. Therefore, aggressive therapy with combinations of these drugs (stacking) should improve the preservation of renal function in DKD.

In praise of pioglitazone: An economically efficacious therapy for type 2 diabetes and other manifestations of the metabolic syndrome.

Pioglitazone improves glycaemic control, not only by lowering insulin resistance, but also by improving beta cell function. Because of the improved beta cell function the glycaemic control that occurs with pioglitazone is prolonged. Pioglitazone has positive effects not only on cardiac risk factors and surrogate measures of cardiovascular disease, it also lowers the incidence of cardiac events in patients with diabetes. The recurrence of transient ischaemic attack and ischaemic stroke is also reduced in non-diabetic, insulin-resistant subjects. Utilized at preclinical stages (but not later) of heart failure, pioglitazone improves diastolic function and avoids progression to heart failure. Pioglitazone, through suppression of atrial remodelling, also decreases the incidence of atrial fibrillation. The manifestations of diseases associated with insulin resistance (non-alcoholic steatohepatitis and polycystic ovary disease) are also improved with pioglitazone. Pioglitazone may possibly improve psoriasis and other dermopathies. Pioglitazone is therefore an inexpensive and efficacious drug for the insulin-resistant subject with diabetes that is underutilized because of biases that have evolved from the toxicities of other thiazolidinediones.

Management of the 'wicked' combination of heart failure and chronic kidney disease in the patient with diabetes.

Patients with type 2 diabetes are at an increased risk of developing heart failure and chronic kidney disease. The presence of these co-morbidities substantially increases the risk of morbidity as well as mortality in patients with diabetes. The clinical focus has historically centred around reducing the risk of cardiovascular disease by targeting hyperglycaemia, hyperlipidaemia and hypertension. Nonetheless, patients with type 2 diabetes who have well-controlled blood glucose, blood pressure and lipid levels may still go on to develop heart failure, kidney disease or both. Major diabetes and cardiovascular societies are now recommending the use of treatments such as sodium-glucose co-transporter-2 inhibitors and non-steroidal mineralocorticoid receptor antagonists, in addition to currently recommended therapies, to promote cardiorenal protection through alternative pathways as early as possible in individuals with diabetes and cardiorenal manifestations. This review examines the most recent recommendations for managing the risk of cardiorenal progression in patients with type 2 diabetes.

Heart failure and diabetes: Clinical significance and epidemiology of this two-way association.

People with type 2 diabetes (T2DM) and those with prediabetes have an increased risk of heart failure (HF). Longer duration of T2DM correlates with a greater risk of HF, but HF is also seen in patients with recent-onset diabetes. Insulin resistance is more likely to be present in patients with HF. The risk of HF persists even in the face of standard-of-care preventive treatments for atherosclerotic cardiovascular (CV) disease. HF is commonly the presenting symptom of CV disease in people with diabetes and is the most expensive complication of diabetes because of the high cost of hospitalizations. Recently hospitalization for HF has been included in CV outcome trials (CVOTs), including for medications that are used to treat T2DM, which has led to new therapies for all HF patients. In addition, these CVOTs have shown that many drugs used in the therapy of diabetes are either neutral or detrimental in the HF patient and should be used with caution in patients with existing HF or those at high risk of HF. Most recently, sodium-glucose cotransporter-2 receptor blockers have shown efficacy in both HF with reduced ejection fraction (EF) and HF with preserved EF. The only other oral or injectable diabetes agent shown to improve outcomes in both is metformin.

Detecting and treating the protean manifestations of diabetic autonomic neuropathy.

The manifestations of diabetic autonomic neuropathy (DAN) are protean and clinically involve multiple systems, including the cardiovascular system, the gastrointestinal system, the genitourinary system as well as the sweat glands (sudomotor dysfunction) and the gallbladder. In addition, cardiac autonomic neuropathy (CAN) is associated with a correctible inability to appreciate and correct hypoglycaemia. While not a clinical problem, pupillary involvement should be the clue and the catalyst to investigate for other manifestations of DAN. This review outlines a practical approach to detecting and investigating the manifestations of DAN. Of particular importance is early detection of cardiovascular involvement where prompt therapy through glycaemic control can decrease the severity of CAN and decelerate the frequency and severity of retinopathy and nephropathy in addition to decreasing cardiovascular events and mortality. CAN also plays a role in accelerating other diabetic complications such as acute ischaemic stroke, heart failure, medial artery calcinosis, foot ulcers, peripheral artery disease and Charcot joints. Many therapies of DAN are available, which should not only decrease morbidity and mortality from DAN, but also improve the patient's quality of life. However, the therapies available are largely symptomatic.

Combine and Conquer: With Type 2 Diabetes Polypharmacy Is Essential Not Only to Achieve Glycemic Control but Also to Treat the Comorbidities and Stabilize or Slow the Advancement of Diabetic Nephropathy.

The concept of polypharmacy in the type 2 diabetic patient is both historic and redundant. A combination of three or more medications usually at doses which are less than those utilized for monotherapy is efficacious not only in the therapy of hyperglycemia but also in the therapy of the comorbidities of hypertension and hyperlipidemia. In addition, multiple medications are now accepted as being necessary to reduce albuminuria and decelerate the decline in renal function in the patient with diabetic nephropathy.

Diabetic Mononeuropathies and Diabetic Amyotrophy.

This brief review describes the etiology, pathophysiology, clinical features, therapy and prognosis of the diabetic mononeuropathies and diabetic amyotrophy and neuropathic cachexia. Mononeuropathies include cranial neuropathies, of which the oculomotor nerve is most commonly affected, and are thought to be due to microvascular occlusion. Peripherally, entrapment neuropathies occur in both the upper and lower limbs and are due to compression of an already damaged nerve in anatomically restricted channels. Diabetic radiculopathies occur in the dermatones of the thorax and abdomen, mimicking intraabdominal or intrathoracic pathology. I also describe the features of the rare but very distinctive diabetic amyotrophy and neuropathic cachexia. Overall, the prognosis from these conditions is excellent with residual pain or muscle weakness being rare with the exception of diabetic amyotrophy where the prognosis is dependent upon cooperation with intensive rehabilitation. Therapies include "watchful waiting," physical therapy and rarely surgical intervention, which may be urgently needed for nerve decompression and reversal of motor defects.

Metformin-induced vitamin B12 deficiency can cause or worsen distal symmetrical, autonomic and cardiac neuropathy in the patient with diabetes.

Metformin blocks the absorption of vitamin B12 through a mechanism that has not been established but could be because of interference with the calcium-dependent binding of the intrinsic factor vitamin B12 complex to the cubam receptor in the terminal ileum. The subsequent deficiency of vitamin B12 may cause or accelerate distal symmetrical and autonomic neuropathy in the patient with diabetes. Several observational studies and meta-analyses have reported a significant association between metformin utilization and vitamin B12 deficiency. Prospective studies have shown that not only do metformin utilizers have lower vitamin B12 levels but they also have higher frequencies of distal symmetrical polyneuropathy and autonomic neuropathy (including cardiac denervation, which is associated with increased incidences of cardiac arrhythmias, cardiac events and mortality). Therefore, periodic monitoring of vitamin B12 is recommended in all patients who utilize metformin, particularly if metformin has been used for over 5 years at which stage hepatic stores of vitamin B12 would probably be depleted. Factors that accelerate the loss of hepatic vitamin B12 stores are proton pump inhibitors, bariatric surgery, being elderly and having an increased turnover of red blood cells. If serum vitamin B12 levels are borderline, measurement of methylmalonic acid and homocysteine levels can detect vitamin B12 deficiency at its earliest stage. Therapies include prophylactic calcium and vitamin B12 supplements, metformin withdrawal, replenishing vitamin B12 stores with intramuscular or oral vitamin B12 therapy and regular monitoring of vitamin B12 levels and vitamin B12 supplements if metformin continues to be utilized. With adequate vitamin B12 replacement, while symptoms of neuropathy may or may not improve, objective findings of neuropathy stabilize but do not improve.

Testosterone Deficiency is Not Protective Against the Development of Adenocarcinoma of the Prostate in a Type 1 Diabetic Patient.

We present a case of prostate cancer (PC) developing in a hypogonadal patient with well-controlled type 1 diabetes. The purpose of reporting this case is to emphasize that regular prostate examinations and prostate-specific antigen (PSA) measurements should be preformed in the diabetic male, even though the incidence of PC is lower in this group of patients. In addition, these examinations and tests need to be preformed even in the hypogonadal patient with diabetes since the presence of a low serum testosterone (T) level does not preclude the development of PC. This is because the development of PC is not related to serum androgen levels but to the androgen levels within the prostate, and dihydrotestosterone (DHT) levels and not T levels within the prostate gland are responsible for the development of PC. In the hypogonadal male, intraprostatic DHT may be high since DHT can be formed from adrenal androgens, particularly androstenedione, through activation of 5α-reductase 2, which is the minority enzyme in the normal prostate but becomes the major enzyme in the formation and growth of PC.

Are the Protean Effects of Pentoxifylline in the Therapy of Diabetes and Its Complications Still Relevant?

Pentoxifylline (Px) has protean effects that can be utilized in the therapy of diabetes and its complications. There have been well-documented but often inconclusive improvements in peripheral arterial disease, foot ulcers, peripheral neuropathy, nephropathy, retinopathy, ischemic heart disease and cerebrovascular disease. In addition, non-alcoholic steatosis and steatohepatitis, which are closely associated with insulin resistance and type 2 diabetes, have been shown to improve with pentoxifylline. Surprisingly, pentoxifylline modestly improves insulin resistance through improvements in capillary blood flow as well as beta cell function and decreased hepatic glucose production. The therapeutic effects of pentoxifylline are complementary to the effects of drugs such as blockers of the renin-angiotensin-aldosterone system when utilized in the therapy of diabetic nephropathy.

Development of Exogenous Insulin Antibody Syndrome in a Patient with Newly Diagnosed Type 1 Diabetes Successfully Treated with Oral Immunosuppressive Monotherapy.

Exogenous insulin antibody syndrome (EIAS), which rarely occurs in the patient with type 1 diabetes, results in antibody-induced insulin resistance, hyperglycemia, ketosis, ketoacidosis, and hypoglycemia when insulin is released from the saturated insulin antibodies. Recommended treatment regimens include glucocorticoids, immunosuppressants, and plasmapheresis. In the patient with type 1 diabetes, glucocorticoids may by inducing and/or worsening ketoacidosis be contraindicated. With immunosuppressants, various anecdotal treatment regimens have been reported. Currently the most commonly recommended regimen is intravenous immunosuppressive therapy in combination with oral immunosuppressants. Herein we describe a patient in whom oral immunosuppressant monotherapy with mycophenolate resulted in the cure of EIAS, thus avoiding the expense associated with intravenous immunosuppressant therapy and/or hospitalization for plasmapheresis.

Alcohol Consumption as a Causator and/or an Accelerator of Neuropathy in People With Diabetes Is Regularly Overlooked.

Patients with diabetes and distal symmetrical polyneuropathy (DSP) are routinely evaluated for etiologies other than diabetes, including vitamin B12 deficiency, paraproteinemia, hypothyroidism and drug or autoimmune-induced neuropathy. However, the most common cause of DSP, next to that of diabetes, is alcohol intake, which is almost never evaluated. In addition to assessment of alcohol intake based on patient history, which often leads to an underestimation of alchohol intake, markers of a high alcohol intake (elevated liver enzymes, uric acid, triglycerides, low magnesium or low folic acid levels) should be obtained. However, the test that is most likely to detect surreptitious alcohol intake is urinary ethyl glucuronide (EtG), which will detect the intake of alcohol within the previous 90 h. Detection of alcohol use is important since if alcohol consumption is not discontinued, DSP, whatever the etiology, will not improve. In addition, the use of drugs to improve symptoms of DSP (tricyclics, anti-epileptics, serotonin, norepinephrine reuptake inhibitors and analgesics) may in combination with alcohol excessively suppress respiration and cognitive function such that these drugs should not be prescribed or utilized if use of alcohol continues. In the future, all patients with DSP, and especially those with symptomatic DSP, should be biochemically screened for excessive alcohol intake and appropriate action taken.

Diabetogenic effects of cardioprotective drugs.

Drugs that protect against cardiovascular events in the patient with diabetes may also positively or negatively affect glycaemic control in the patient with established diabetes and may induce the development of diabetes in the predisposed patient. Mainly through increasing insulin resistance, beta-blockers, statins and high-dose diuretics have the potential to worsen glycaemic control. Dihydropyridine calcium channel blockers, low-dose diuretics, vasodilating beta-blockers, alpha-blockers and pitavastatin have little or no effect on glycaemic control. Blockers of the renin-angiotensin-aldosterone system, colesevelam, ranolazine and verapamil, through slowing breakdown of bradykinin, vasodilation, increasing cholecystokinin levels, blocking sodium channels and decreasing beta cell apoptosis, may improve glycaemic control and avoid the development of diabetes.

Why Do Falls and Lower Limb Fractures Occur More Frequently in the Diabetic Patient and How Can They Be Prevented?

Due to primarily sarcopenia and hypoglycemia but also neuropathy, hypotension, analgesics and polypharmacy, there is an increased incidence of falls and hip fractures in both the type 1 and type 2 diabetic patient. Utilization of insulin, hypotensive drugs, analgesics and perhaps canagliflozin further increases the risk. Thiazolidinedione use may increase the risk of osteoporosis and fracture. Prolonged hyperglycemia resulting in cross-linking of collagen and advanced glycosylation end products alter the microarchitecture and increase bone fragility. Higher serum vitamin D levels seem to decrease the incidence of both falls and fractures. Following a hip fracture, mortality in the diabetic patient is increased largely because of cardiovascular events and pneumonia. Prevention of sarcopenia includes dietary therapy, vitamin D and testosterone replacement when appropriate.

Stroke in the patient with diabetes (part 1) - Epidemiology, etiology, therapy and prognosis.

There is a higher incidence of stroke in both the type 2 diabetic and the non-diabetic insulin resistant patient which is accompanied by higher morbidity and mortality. The increase in the frequency of stroke is due to an increase in cerebral infarction, mainly lacunar infarcts, with the incidence of cerebral hemorrhage being less frequent. The major risk factors for stroke in the type 2 diabetic patient are age, hypertension, the number of features of the Metabolic Syndrome, the presence of diabetic nephropathy in both the type 1 and type 2 patient, the presence of peripheral and coronary artery disease and especially the presence of atrial fibrillation. Hyperglycemia is associated with a poor outcome from stroke but is not causative.

Stroke in the patient with diabetes (Part 2) - Prevention and the effects of glucose lowering therapies.

There is a higher incidence of stroke in both the type 2 diabetic and the non-diabetic insulin resistant patient which is accompanied by higher morbidity and mortality. Stroke primary prevention can be achieved by controlling atrial fibrillation and hypertension, and the utilization of statins and anticoagulant therapies. Utilizing pioglitazone and GLP-1 receptor agonists reduce the risk of stroke while the utilization of metformin, α-glucosidase inhibitors, DPP-4 and SGLT-2 inhibitors have no effect. Insulin use may be a marker of increased risk of stroke, but not necessarily causative. Utilizing intravenous insulin to normalize plasma glucose levels in the acute phase of a stroke does not improve the outcome. Antiplatelet agents are not proven to be of benefit in primary prevention whereas the use of direct-acting oral anticoagulants to avoid stroke and the early use of tpA in the acute phase have been shown to be beneficial.

Case Report: Efficient Avoidance of Hospitalization for Diabetic Ketosis Utilizing Technosphere Inhaled Insulin.

We describe the use of inhaled insulin for the therapy of diabetic ketosis/ketoacidosis in a patient with type 1 diabetes. In this situation high insulin levels are needed to metabolize ketone bodies and avoid hospitalization. Technosphere inhaled insulin (TI) may be an alternative to subcutaneously injected fast-acting insulins, not only because of its rapid onset of action but also lack of stacking leading to late-onset hypoglycemia. In conclusion, TI may well be more efficacious and safer in the outpatient management of diabetic ketosis/ketoacidosis than standard subcutaneously injected rapid-acting insulin.