Glucose Transporters

Glucose transporters are required from shuttling glucose from the extracellular to intracellular compartment. Insulin by binding to the tyrosine kinase insulin receptor present on target cells promotes the translocation of various sodium glucose transporters from the Golgi apparatus to the cellular membrane.

Distribution of Glucose transporters

Location of Glucose Transporters

The distribution of glucose transporters varies significantly between various tissues.  Insulin is not required for the expression of all glucose transporters. For example, GLUT-2 transporters present in pancreatic islet (beta) cells and hepatocytes are insulin independent. On the other hand, GLUT-4 transporters present in striated muscle and adipose tissues, are insulin dependent and are induced in response to the presence of insulin.

Glucose Transporter Location Comments
GLUT-1 Erythrocytes, blood-brain barrier Low level of basal glucose uptake required to sustain cellular respiration
GLUT-2 Beta cells, renal tubular cells, liver, intestinal epithelial cells  
GLUT-3 Neurons and placenta  
GLUT-4 Striated muscle and adipose tissue ONLY insulin-regulated GLUT : It is responsible for insulin mediated glucose uptake

We found this detailed lecture by AK Lectures (on YouTube) very helpful. Watch this video if you are interested in learning more about the properties of Glucose Transporters.

Thyroid Examination

A thyroid examination is a simple bedside evaluation that will help diagnose thyroid disorders, including hypothyroidism, hyperthyroidism, or both. The thyroid gland is located in your neck below the thyroid cartilage (Adam’s apple). It produces two important hormones: 3,5,3′,5′-tetraiodothyronine (T4) and  3,5,3′-Triiodo-l-thyronine (T3).

There are several different types of thyroid disease, including Hashimoto’s disease (which causes an underactive thyroid gland), Graves’ disease (autoimmune mediated inflammation of the thyroid gland which results in productive hyperthyroidism), or toxic nodular goiter (with benign nodules producing excess thyroid hormone)

Inspection of the thyroid gland

  • A visible anterior neck mass, which is mobile on deglutition, implies an enlarged gland. Offer the patient a glass of water to drink. The normal thyroid gland cannot be visualized on inspection.
  • Positive Pemberton’s sign is suggestive of significant retrosternal extension of a goiter.


  • Optimal positioning of the neck will facilitate palpation of the gland. The patient’s neck should be in a relaxed position, which prevents extensive nuchal extension or flexion. The sternocleidomastoid muscle should not be under tension, and there should be adequate room between the chin and the sternum to allow proper positioning of the hands.
  • Sequentially palpate each thyroid lobe and isthmus. Occasionally there might be an accessory extension of the isthmus – the pyramidal lobe. Check for the consistency of the gland. Avoid deep palpation if the gland is tender, as might occur in De Quervain’s thyroiditis. The normal thyroid has a mild firm consistency. The overlying skin is usually freely mobile over it. If the gland is attached to overlying skin, it might be suggestive of either a malignancy or Riedel’s thyroiditis.
  • Attempt to feel for any discrete thyroid nodule. These are best appreciated using the pulp of your examining fingers (2nd, 3rd, and 4th digits)
  • Ask the patient to swallow during palpation and check for any retrosternal extension of the thyroid gland.
  • Grade thyromegaly with the WHO classification system
  • Palpate all regional lymph node groups (I to VI)


  • Percussion of the sternal manubrium may be required in patients with a suspected retrosternal goiter. The percussion note will be dull. This step is seldom warranted, especially if there is no palpable thyroid tissue extending below the proximal portion of the manubrium (thoracic aperture).


  • In patients with hyperdynamic circulation, as might occur in overt Graves disease, a bruit may be appreciated over the superior poles of the thyroid in the vicinity of the superior thyroid arteries.

Anatomy of the Pancreas

In this article, we will review the embryology, gross anatomy and histology of the pancreas.

Historical timeline of discoveries in diabetes care

  • Around 1500 B. C., Papyrus Ebers, Egypt; description of abnormal polyuria, possibly diabetes mellitus.
  • 6th century B. C. The Indians differentiated the asthenic from the sthenic form of diabetes mellitus. In the Ayur Veda of Susruta, the illness is termed as “madhumeha” or “honey-urine”.
  • A few centuries B. C., the Chinese recognized the sweet taste of the urine.
  • 30 B. C. to 50 A. D. Aulus Cornelius Celsus described a condition in which much urine was excreted.
  • 30 to 90 A. D. Aretaeus Of Cappadocia gave the same description as Celsus and called it “diabetes”.
  • 131 to 201 A. D., Galen (an anatomist) described diabetes as a weakness of the kidneys.
  • 860 to 932 Rhazes, an Arabian physician, discussed the treatment of diabetes mellitus
  • 980 to 1027 Avicenna believed that the liver was particularly affected in diabetes and observed the connection between diabetes, furunculosis, and impotence.
  • 1621 to 1675 Thomas Willis, in Oxford, distinguished diabetes mellitus from diabetes insipidus, and showed that the urinary sugar was increased in the former condition.
  • 1682 Johann Conrad Brunner observed polyuria and polydipsia in a dog after removal of the pancreas.
  • 1774 Robert Wyatt suspected the presence of a substance similar to sugar in the urine and blood. He obtained this substance by evaporating the urine.
  • 1776 Dobson demonstrated a fermentable sugar in the urine and the sweet taste of the blood of diabetic patients.
  • 1788 Thomas Cawley suspected a connection between diabetes and changes in the pancreas.
  • 1796 Rollo recommended a low-calory diet in the treatment of diabetes and described the smell of acetone.
  • 1815 Chevreul identified the sugar in diabetes as glucose.
  • 1806-1886 Bouchardat utilized fermentation tests, the polarimeter and solutions of copper salts, for estimating sugar. He substituted fat and alcohol for carbohydrates, emphasized the value of green vegetables, a low-calorie diet, and much physical activity. He introduced days of fasting and the use of alkali, and discovered gluten bread.
  • 1848 Hermann Von Fehling described the urine test which was later named after him.
  • 1849 Claude Bernard discovered glycogen in the liver, and the “piqure”. He made quantitative estimations of the sugar in the blood.
  • 1869 Paul Langerhans discovered the islet cells of the pancreas.
  • 1882 Chauffard and Hanot described the combination of pigment-cirrhosis and diabetes as “bronze diabetes”.
  • 1889 Von. Recklinghausen revealed the nature of the two pigments of “bronze diabetes”, and introduced the term hemochromatosis.
  • 1889 O. Minkowski and J. Von Mering incidentally discovered that total pancreatectomy in a suitable experimental animal produces diabetes.
  • 1891 Giulio Vassale ligated the excretory ducts of the pancreas, which led to the destruction of the acini, but not of the islet cells.
  • 1892 O. Minkowski produced temporary disappearance of diabetes in dogs by subcutaneous implantation of the excised pancreas.
  • 1893 Laguesse suspected that the islet cells formed a hormone.
  • 1895 v. Noorden developed a technique of dietary therapy, stressed the formation of sugar from protein, and introduced the course of oats as a treatment.
  • 1898~1962 E. P. Joslin untiringly improved the treatment of diabetes mellitus.
  • 1906 Naunyn studied the metabolism in diabetes, particularly in diabetic acidosis. He emphasized the familial occurrence of the disease and the value of a just adequate nourishment in the prophylaxis and in the treatment of the metabolic disturbance.
  • 1908 Zuelzer gained an alcoholic extract from the pancreas, which after being injected, produced shock – probably of hypoglycemic nature – causing the trial to be discontinued.
  • 1909 De Meyer gave the name insulin to the still hypothetical hormone of the islet cells.
  • 1913 F. M. Allen became famous for his hunger cures. He also contributed to the knowledge of carbohydrate metabolism.
  • 1918 C. K. Watanabe produced hypoglycemia in the animal with an injection of guanidine.
  • 1921 N. C. Paulesco in Rumania reported “pancreine”, i.e. a blood sugar-lowering extract from pancreas of dogs or cattle, which he had discovered during the First World War (1914-18).
  • 1921 Frederick G. Banting and Charles H. Best discovered insulin. F. C. Mann and T. B. Magath showed that hepatectomy results in hypoglycemia.
  • 1924 B. A. Houssay and Magenta noticed that hypophysectomy increases sensitivity to insulin.
  • 1924 Seal Harris suspected hyperinsulinism as a cause of spontaneous hypoglycemia.
  • 1926 E. Frank, M. Nothmann, and A. Wagner introduced biguanidines into the treatment of diabetes which, however, was abandoned in 1940. Abel succeeded in crystallizing insulin.
  • 1927 Wilder, Allan, Power, And Robertson published the first case of organic hyperinsulinism.
  • 1929 Howland, Campell, Maltby, and Robinson removed an islet-cell tumor and cured a case of hyperinsulinism for the first time.
  • 1936 H. C. Hagedorn produced the first reliable insulin with prolonged action.
  • 1937 F. G. Young discovered meta-pituitary diabetes. H. R. Jacobs observed alloxan-hyperglycemia.
  • 1942 Guest pointed out hypokalemia during the treatment of diabetic acidosis.
  • 1942 M. Janbon noticed the hypoglycemic action of one of the sulfonamides recommended for the treatment of typhoid fever.
  • 1943 Dunn, Sheehan, and Macletchie discovered alloxan-diabetes.
  • 1944 A. Louba Tieres explained the mode of action of certain hypoglycemic agents
  • 1955 H. Franke and J. Fuchs observed hypoglycemia produced by another sulfonamide, and suggested that it should be used therapeutically in diabetes mellitus.
  • 1955 F. Sanger discovered the structural formula of the insulin molecule.
  • 1957 G. Unger introduced phenethyl biguanide into the treatment of diabetes.
  • 1957 S. A. Berson and R. S. Yallow measured the insulin content of the plasma by radioimmunological
  • methods.
  • 1964 H. Zahn in Germany, Katsoyannis in U.S.A, and Niu Ching-I in China (1965), all independently succeeded in synthesizing insulin.
  • 1967 D. F. Steiner and P. Oyer isolated proinsulin.
  • 1969 Mrs. D. G. Hodgkin discovered the three-dimensional structure of pig insulin.

Embryology and Histology of the Pancreas

In the human embryo (measuring 3 to 4 mm in length), two entodermal outpocketings arise on opposite sides of the primitive duodenum. One of the epithelial buds grows out from the dorsal wall of the gut, just above the hepatic diverticulum; it forms the dorsal pancreas. The ventral pancreas, on the other hand, originates in the caudal angle between hepatic diverticulum and gut.

When the embryo is about 12 mm long, the two primordia meet, and when it is about 16 mm, they fuse to produce a joint organ. With the exception of the major parts of the head and the uncinate process, which are derivatives of the ventral bud, most of the mature gland is formed by the dorsal pancreas anlage. Both primordia are crossed by an axial longitudinal duct.

Anatomy of the Pancreas. Don Blis (artist), Public domain, via Wikimedia CommonsAnatomy of the Pancreas. Don Blis (artist), Public domain, via Wikimedia Commons

The duct of the dorsal anlage originates directly from the wall of the duodenum, whereas the ventral duct opens into the stem of the elongating common bile duct. When duodenal torsion has brought the two primordia into close side-by-side contact, the ventral duct taps its dorsal counterpart. The major pancreatic duct of the mature gland (duct of Wirsung) results, therefore, from the fusion of the ventral duct with the distal segment of the dorsal duct. The proximal stem segment of the dorsal duct, on the other hand, constitutes the accessory duct of Santorini, which usually retains its connection to the duodenum as well.

The islets of Langerhans develop from epithelial cells ofthe outgrowing pancreatic ducts. They are, therefore, of entodermal origin. Even in the embryo of 18 mm in length (age about 7 weeks), the terminal and side buds of the primitive ducts contain a few granular cells which can be selectively blackened by silver-salt solutions. These cells multiply and form single solid sprouts which enlarge to become the fetal (and early post-natal) islets.

A high-resolution photomicrograph of a pancreas islet (Islet of Langerhans). Stain: Hematoxylin and EosinA high-resolution photomicrograph of a pancreas islet (Islet of Langerhans). Stain: Hematoxylin and Eosin. The endocrine pancreatic islet appears as a pale-staining complex in the middle of the field. It lies on a background of deeply staining pancreatic secretory acini (exocrine pancreas). Also, the pancreatic islet contains a rich vascular supply (capillaries) and multiple islet cells encased in a thin connective tissue capsule.

These so-called primary islets consist of a central mass of insulin-producing Beta cells which are surrounded by a compact layer of glucagon-synthesizing alpha cells. Between these two subdivisions, a transitional zone containing agranular cells soon develops. The core of the islet thus enlarges considerably and the islet itself resembles more and more the one found in the adult pancreas. The mature islets of Langerhans are rounded or ovoid epithelial complexes usually situated in the central portions of the lobules of the exocrine pancreas.

They may also, however, be found in the interlobular connective tissue or associated with the smaller branches of the pancreatic ducts. Although the islets are scattered throughout the exocrine pancreatic parenchyma, they are more numerous in the tail than in the head or body of the gland. The highly vascularized islets receive their blood supply through branches of the interlobular arteries which arise from both the celiac trunk and the superior mesenteric artery. The thin capsule of reticular fibers separating the islets from the exocrine parenchyma is usually penetrated by one arteriole. Within the islet, this arteriole splits up into a number of anastomosing capillary loops which are in intimate contact with the epithelial cords, like the vas afferens in a kidney glomerulum. The endothelium of these capillaries varies considerably in thickness. In attenuated portions of the endothelial cells, typical fenestrae (endothelial pores) are present.

Table . Pancreatic islet cells and their corresponding hormones

Islet cell (frequency)Hormone producedEffects(s)
Beta cells (50-70%)Insulin and amylinInsulin increases peripheral glucose uptake and reduces hepatic gluconeogenesis and glycogenolysis.
Amylin slows gastric emptying and stimulates satiety
Alpha cells (20-30%)GlucagonStimulates hepatic gluconeogenesis and glycogenolysis. Stimulates hepatic ketogenesis during a prolonged fast
Delta cells (10%)SomatostatinInhibits the secretion of insulin, glucagon, and PP
PP cells (2%)Pancreatic polypeptideInhibition of glucagon secretion and acts as a satiety hormone
Epsilon cells (1%)GhrelinInhibits insulin release after a glucose load. Stimulates GH secretion and is also called the "hunger hormone."
G cells (absent)GastrinPancreatic gastrin-producing cells are present during embryonic development but undergo involution in adults. Re-expression of gastrin can, however, occur in the setting of pancreatic neuroendocrine tumorigenesis (Zollinger-Ellison Syndrome).
EC cells (rare)SerotoninClassic features of carcinoid syndrome

Light microscopy reveals that the islet cells are less stainable than the acinar cells of the exocrine pancreas. In hematoxylin and eosin preparations, the cytoplasm of these cells appears more or less homogeneous, but with the Malloryazan stain, three types of cells can be easily distinguished, all of them displaying distinct granules in their cytoplasm. The alpha-cells, which are found predominantly at the periphery of the islets, contain granules which stain red and are insoluble in alcohol. The somewhat smaller granules of the more centrally located beta-cells, on the other hand, stain orange and are dissolved in alcohol. A third cell type, the so called delta-cell, is scattered throughout the islet. It displays granules which stain blue.

 Electron microscopy shows that the alpha cells contain large numbers of membrane-bound, electron-dense granules. Characteristically, the granules are separated from their membrane by a very narrow, electron-translucent cleft. In human beta-cells, some of the granules contain rounded or polygonal crystalloid structures which display an internal periodicity.

The mitochondria of this cell type appear to be more numerous than in the alpha cells. The Golgi complex is well-developed. Between the granules, elongated and vesicular profiles of the rough-surfaced endoplasmic reticulum are intermingled with free ribosomes and small vesicles. The granules of the delta cells are larger and much less electron-dense than those of the alpha and beta cells.


Ferri V, Vicente E, Quijano Y, Ielpo B, Duran H, Diaz E, Fabra I, Caruso R. Diagnosis and treatment of pancreas divisum: A literature review. Hepatobiliary Pancreat Dis Int. 2019 Aug;18(4):332-336.

A-Kader HH, Ghishan FK. The Pancreas. Textbook of Clinical Pediatrics. 2012:1925–36. 

Kimura W. Surgical anatomy of the pancreas for limited resection. J Hepatobiliary Pancreat Surg. 2000;7(5):473-9.

GKI regimen

The GKI or GIK regimen is a simple and effective combined insulin delivery method that has gained wide acceptance in the perioperative management of diabetic patients who would require Nil Per Oral (NPO) status. The GKI regimen can be used in patients with either type 1 or type 2 diabetes mellitus in the perioperative period.

It involves the continuous intravenous administration of insulin, glucose, and potassium as a single infusion. GKI is typically initiated on the morning of the surgery and continued until the patient resumes regular oral feeding.

Origin of the GKI regimen

The GIK or GKI regimen is based on the classic Alberti regimen, a treatment protocol for managing diabetes that involves administering glucose, insulin, and potassium. This approach was developed by Thomas and Alberti in the 1980s  and has been proven effective in controlling blood sugar levels in patients with diabetes.

The GKI infusion regimen is based on the following metabolic principles

  • A 70kg adult requires approximately 180 grams of glucose per day for both nervous system and red cell function (About 7.5 grams of glucose per hour)
  • Insulin drives serum potassium into cells, increasing the risk for hypokalemia
  • An insulin sensitivity factor of 1 unit for every 25mg/dl of capillary glucose

Remembering the components of the GKI infusion bagA simple mnemonic or memory aid is the rule of 10s. 10% Dextrose, 10units of regular insulin, and 10mEq KCl

GKI protocol (The Classic Alberti Regimen)

The Alberti Regimen (1979) combines regular insulin, dextrose, and potassium in a single infusion. This helps to prevent inadvertent insulin infusion without dextrose, thus reducing the risk of hypoglycemia.

The amount of insulin added to a bag is dependent on the patient’s capillary glucose. For this reason, new mixtures of regular insulin with potassium and dextrose should be prepared when a dose change in insulin is needed.

Caution : It is worth noting that aspart, lispro, glulisine insulin CANNOT be administered intravenously. These insulins are only appropriate for subcutaneous administration.

On the morning of surgery, set up 500ml of 10% dextrose, 10 units of regular insulin, and 10 mmol of potassium chloride (Kcl). The recommended initial infusion rate is 100 ml per hour. Blood glucose should be checked every 1-2hours perioperatively. Capillary glucose guides subsequent changes in the GKI bag. Thus, the rate of infusion remains constant; however, the dose of regular insulin varies based on capillary glucose. See the infographic section below.

Before Surgery

  • Do not administer any insulin secretagogues on the morning of surgery
  • Discontinue metformin before surgery
  • Set up an infusion of 500ml of 10% Dextrose, 10units of regular insulin, and 10mEq of potassium chloride (KCl). We will refer to this as the standard GKI. GKI should be initiated at least 30 minutes prior to surgery.

During surgery

  • Start the infusion rate at 100ml per hour and monitor capillary glucose hourly throughout the surgery in order to maintain glycemic control. The subsequent infusion rate will be dependent on capillary blood glucose (checked at least every hour).

Capillary glucose mmol/L (mg/dL)Regimen
5-10 mmol/L (90-180mg/dL)Continue Standard GKI at 100ml per hour
<3.9 mmol/L (70mg/dL)STOP infusion. Administer IV bolus of 50% Dextrose in water (25ml)
<5 mmol/L (90mg/dL)Change bag to 500 ml of 10% Dextrose, 10mEq of KCl + 5 units of regular insulin, @100ml per hour
>10 mmol/L (180mg/dL)Change bag to 500 ml of 10% Dextrose, 10mEq of KCl + 15 units of regular insulin, @ 100ml per hour
>20 mmol/L (360mg/dL)Change bag to 500 ml of 10% Dextrose, 10mEq of KCl + 20 units of regular insulin, @ 100ml per hour

After surgery

  • Continue 4-5 hourly infusions of the glucose potassium insulin bag (500ml at 100cc per hour) and monitor capillary blood glucose every 4 hours and plasma potassium every 8 hours. If smaller volumes of fluids have to be administered due to a change in the patient’s clinical status, then equivalently lower volumes of either 20% or 50% Dextrose may be used (via a central line due to the higher concentration and risk for phlebitis!)
  • Stop the GKI infusion when oral feeding is resumed and switch to multiple daily insulin injections. Do NOT use a reactive sliding scale only for a diabetic patient who has resumed oral feeding.
  • If oral feeding cannot be resumed within 48-72hours, as might occur with critically ill patients, consider parenteral nutrition.

The Modified Alberti Regimen

The modified Alberti Regimen is much simpler since the optimal glucose range is much broader (120-200mg) and requires no change in the bag when capillary glucose is in this range. This will mean less frequent changes in GKI bags.

On the morning of surgery, set up 500ml of 10% dextrose, 15 units of regular insulin (slighter higher dose than the classic Alberti regimen), and 10 mmol of potassium chloride (Kcl).

The recommended initial infusion rate is 100 ml per hour. Blood glucose should be checked every 1-2hours perioperatively.

Capillary glucose mmol/L (mg/dL)Regimen
6.7 – 11.1 mmol/L (120-200 mg/dL)Continue Modified Alberti (GKI bag - 500ml of 10% Dextrose, 15units of Regular Insulin and 10mEq of potassium chloride) at 100ml per hour
< 6.7 mmol/L (120mg/dL)Change bag to 500 ml of 10% Dextrose, 10mEq of KCl + 10 units of regular insulin, @100ml per hour
> 11.1 mmol/L (200mg/dL)Change bag to 500 ml of 10% Dextrose, 10mEq of KCl + 20 units of regular insulin, @100ml per hour

Caveats to applying the GKI regimen

  • Patients who are septic or undergoing cardiac bypass surgery typically have higher insulin requirements in the perioperative period.
  • If the infusion is stopped for more than 30 minutes, the patient’s extracellular fluid will have inadequate exogenous insulin; thus, close monitoring is required. This is even more relevant for patients with type 1 diabetes mellitus. Without any background basal insulin, these patients can go into rapid diabetic ketoacidosis!
  • As with all things in medicine, specifically diabetes care, every patient is unique. Therefore, common sense and clinical judgment are required when starting the standard GKI regimen.

Simple Infographics for the Classic Alberti GKI regimen

The infographics below depict suggested infusion rates depending on blood glucose levels. Scales of measurement in either mg/dl or mmol/L.

GKI in mg per dlGKI regimen in mmol per L

  • What is the rule of 10s for the GKI (Alberti) infusion?

    This refers to a bag of 500ml of 10% Dextrose, 10units of regular insulin, and 10mEq of potassium chloride (KCl).

  • When should the GKI infusion be started?

    GKI should be initiated at least 30 minutes prior to surgery.

  • When should the GKI infusion be stopped?

    Stop the GKI infusion when oral feeding is resumed and switch to multiple daily insulin injections.


Images(s) Courtesy


Dermatologic manifestations of diabetes mellitus

The prevalence of cutaneous manifestations of diabetes mellitus (both Type 1 and Type 2) ranges between 30 to 70%. The clinical features and underlying mechanism of these dermatologic features of diabetes mellitus will be described next.

Acanthosis nigricans

DescriptionPoorly delineated plaques with a grey to dark-brown pigmentation. Typically has a velvety texture.
LocationIntertriginous and other flexural areas (axilla, elbows, inframammary regions, palms – known as “Tripe palms”).
Mechanism• Insulin activates IGF-1 receptors present on fibroblasts and keratinocytes
• Additionally, hyperinsulinemia causes a decrease in IGF binding proteins, which results in a higher level of unbound (active) IGF-1 (vicious cycle)
• Androgens and growth factor receptors are present on keratinocytes and fibroblasts as well (may explain other hormonal causes of acanthosis nigricans)
Treatment• Improvement in insulin resistance (metformin, dietary changes, increased physical activity, and weight reduction)

Acanthosis nigricans

Diabetic dermopathy

DescriptionHyperpigmented and circumscribed red papules that change over 1-2 weeks into atrophic brown papules
LocationPretibial area
MechanismNeuropathy and microangiopathy induced by uncontrolled diabetes mellitus
TreatmentIt is self-limited and largely asymptomatic, as such treatment is not required

Diabetic dermopathy

Acrochordons (skin tags)

DescriptionPedunculated cutaneous fibromas
LocationFlexural areas in the neck and axilla, in a pattern akin to the distribution of acanthosis nigricans
MechanismHyperinsulinemia promotes the activation of fibroblast bound IGF-1 receptors present in the epidermis. This is followed by the proliferation of skin fibroblasts and subsequent development of skin tags.
TreatmentNo treatment is required

Necrobiosis lipoidica diabeticorum (NLD)

DescriptionA red-brown papule that progressively increases in diameter and eventually changes into the classic waxy, yellowish lesion. There is occasional central ulceration, which manifests as an atrophic center. Exhibits Koebnerization.
LocationPresent almost always on pretibial areas of the lower extremities
MechanismThere is initial tissue hypoperfusion in the skin due to microangiopathy involving skin capillaries. Microangiopathy occurs as a result of the accumulation of advanced glycated end products in the vasculature, which consequently promotes local oxidative stress. Inflammatory mediators which have accumulated in response to tissue hypoperfusion lead to a progressive breakdown in collagen
TreatmentTopical or intra-lesional corticosteroids

Necrobiosis lipoidica diabeticorum


DescriptionLocalized lipodystrophy due to insulin injections is an umbrella term that consists of the lipoatrophy (LA) and lipohypertrophy (LH) subtypes. LA tends to appear as an area of subcutaneous tissue loss, which creates a dimple in the skin. LH, however, has a firm, rubbery consistency that is palpable in the subcutaneous tissue plane. Occasionally, LH lesions may be soft, making them difficult to discern on routine physical examination.
LocationSites of insulin injections
Mechanism• Lipoatrophy occurs as a result of an immune-mediated reaction to insulin; it is less prevalent now due to the use of modern human insulin or human-like insulin analogs.
• Lipohypertrophy is due to the growth-promoting effects of insulin on fibroblasts in the subcutaneous tissue. Insulin binds to IGF-1 receptors on fibroblasts which leads to the activation and subsequent proliferation of fibroblasts
TreatmentRotation of sites of insulin injection

Bullosis Diabeticorum

DescriptionSudden onset of one or more non-erythematous, firm and sterile bullae containing a clear fluid. They may range in size from 0.5cm to 5cm.
LocationUsually located on the lower extremities
TreatmentThese can be aspirated for symptomatic relief.

Scleroderma diabeticorum

DescriptionThickened, waxy, or edematous indurated plaques
LocationDistributed over the neck and upper back. Diabetic hand syndrome, a form of scleroderma-like skin change of diabetes, may present with limited joint mobility, palmar fibromatosis (Dupuytren's contracture), or stenosing tenosynovitis (“trigger finger”)
MechanismReduced breakdown of collagen fibers due to nonenzymatic glycosylation of dermal collagen

Eruptive xanthoma

DescriptionYellowish papules
LocationLocated over the trunk and extensor surfaces such as the elbows and knees.
MechanismReduced lipoprotein lipase activity due to insulin resistance or insulinopenia causes impaired storage of triglycerides in adipose tissue. As a consequence, triglycerides accumulate in the skin.
TreatmentTreatment of diabetes. Surgical treatment in select cases

Download Dermatologic manifestations of diabetes mellitus ppt (powerpoint format)


Duff M, Demidova O, Blackburn S, Shubrook J. Cutaneous manifestations of diabetes mellitusClin Diabetes. 2015;33(1):40-48. 

Images(s) Courtesy

Masryyy, CC BY-SA 4.0 , via Wikimedia Commons (Acanthosis nigricans)

Hypoglycemia after Gastric Bypass

Hyperinsulinemic hypoglycemia is a complication of gastric bypass surgery and may occur anywhere from 6 months to 8 years after surgery. The definition, diagnostic criteria, pathophysiology mechanisms, and treatment will be reviewed.

Definition of hypoglycemia

Hypoglycemia is defined as a low plasma glucose (< 50–55 mg/dl) in the presence of symptoms compatible with neuroglycopenia that are ameliorated by a glycemic load (Whipple’s triad).

Diagnosis of post gastric hypoglycemia

  1. Fulfillment of Whipple’s triad
  2. Concomitantly elevated insulin (> 3 μU/ml) and C-peptide (> 0.6 ng/ml) ***
  3. Negative oral hypoglycemic agent screen or exposure to exogenous insulin.

*** It is worth knowing that c-peptide has a biological half life of approximately 30 minutes, as such, in the postprandial period, c-peptide may still be elevated in “normal” patients (even if endogenous insulin which has a half life of a few minutes is appropriately suppressed). A liquid mixed-meal test which requires the measurement of c-peptide levels is also fraught with challenges in interpreting c-peptide levels.

Differential diagnoses of hypoglycemia after gastric bypass surgery

The differential diagnoses of hypoglycemia after gastric bypass surgery include dumping syndrome (both early and late dumping),hyperinsulinemic hypoglycemia and rarely, insulinoma)

Dumping Syndrome

Dumping syndrome occurs in up to 50% of post gastric bypass patients. Ingestion of simple sugars is the usual trigger for this syndrome in the post gastric period.

Early dumping – This occurs as a result of rapid emptying of food into the jejunum because of the surgically altered gastrointestinal anatomy. Patients present with vasomotor symptoms (flushing, tachycardia and diaphoresis), colicky bdominal discomfort, and diarrhea. Early dumping occurs soon after the gastric bypass surgery but improves over time.

Late dumping – This is a form of “reactive hypoglycemia,” which occurs at least one to three hours after meal ingestion. It occurs as a consequence of the rapid release of insulin in response to hyperglycemia. Late dumping occurs as a result of absorption of simple sugars from the proximal small intestine.

Treatment : Patients with either early or late dumping respond to nutrition modification, which involves the ingestion of frequent, small and low-carbohydrate meals. Pharmacotherapeutic options include acarbose and somatostatin

Post-RYGB hypoglycemia (hyperinsulinemic hypoglycemia)

Presents several months to years (usually > 1 year) after gastric bypass surgery. The underlying mechanism is pancreatic nesidioblastosis.

Pancreatic nesidioblastosis is characterized by islet cell enlargement and increased budding of β-cells from ductal epithelium. This condition may also in patients with no history of gastric bypass surgery.

Treatment : This condition responds suboptimally to carbohydrate restriction alone. Pharmacotherapies include α-glucosidase inhibitor acarbose, octreotide, verapamil, and diazoxide.

For patients with debilitating symptoms and a positive selective arterial calcium-stimulated test, partial pancreatectomy may lead to significant amelioration of symptoms. In some instances, RYGB may have to be reversed (restoration of normal intestinal anatomy)


Although insulinomas typically cause fasting hypoglycemia, postprandial hypoglycemia may occur in up to 10% of patients.

Treatment of hypoglycemia after gastric bypass

DrugMechanism of Action
DiazoxideDiminishes insulin secretion. It causes marked edema and hirsutism
OctreotideOctreotide is an analog of somatostatin (exhibits growth hormone-inhibitory function). Although octreotide inhibits growth hormone secretion, in large doses, it also inhibits the secretion of thyroid-stimulating hormone (TSH), insulin, and glucagon. Variable efficacy in patients with hyperinsulinemic hypoglycemia.
EverolimusEverolimus is an inhibitor of the mammalian (mechanistic) target of rapamycin (mTOR)
Verapamil A calcium channel blocker with reported efficacy in the management of hypoglycemia. Limited by its hypotensive effects.


Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER, Service FJ; Endocrine Society. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2009 Mar;94(3):709-28.